Akt: versatile mediator of cell survival and beyond.

The serine/threonine kinase Akt has been intensely studied for its role in growth factor-mediated cell survival for the past 5 years. On the other hand, the ongoing research effort has recently uncovered novel regulatory mechanisms and downstream effectors of Akt that demonstrate the involvement of Akt in other cellular functions such as cell cycle progression, angiogenesis, and cancer cell invasion/metastasis. Furthermore, recent studies using whole model organisms suggest additional roles for Akt in important diseases such as aging and diabetes. The following review addresses these recent advances in the understanding of Akt function.

[1]  H. Kalthoff,et al.  Molecular mechanisms of tumor metastasis and angiogenesis , 1999, Langenbeck's Archives of Surgery.

[2]  A. Weiss,et al.  Induction of NF-κB by the Akt/PKB kinase , 1999, Current Biology.

[3]  Andrius Kazlauskas,et al.  The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase , 1995, Cell.

[4]  B. Groner,et al.  Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. , 1997, Immunity.

[5]  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 .

[6]  E. Wilder,et al.  Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB , 1999, Nature Cell Biology.

[7]  J. Cheng,et al.  AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  H. Koh,et al.  Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  M. Goligorsky,et al.  CO‐OPERATION BETWEEN ENDOTHELIN AND NITRIC OXIDE IN PROMOTING ENDOTHELIAL CELL MIGRATION AND ANGIOGENESIS , 1999, Clinical and experimental pharmacology & physiology.

[10]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[11]  J. Cheng,et al.  Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Do,et al.  Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit* , 1999, The Journal of Biological Chemistry.

[13]  R. Schwartz,et al.  Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway. , 2000, The Journal of biological chemistry.

[14]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[15]  W. Sessa,et al.  Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. , 2000, Circulation research.

[16]  J. York,et al.  Tyrosine 1101 of Tie2 Is the Major Site of Association of p85 and Is Required for Activation of Phosphatidylinositol 3-Kinase and Akt , 1998, Molecular and Cellular Biology.

[17]  G. Cooper,et al.  Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. , 1995, Science.

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

[19]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

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

[21]  K. Imahori,et al.  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 , 1996, Neuroscience Letters.

[22]  David R. Kaplan,et al.  Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate , 1997, Science.

[23]  Marty W. Mayo,et al.  NF-k B Antiapoptosis : Induction of TRAF 1 and TRAF 2 and c-IAP 1 and c-IAP 2 to Suppress Caspase-8 Activation , 1998 .

[24]  Emmett V Schmidt,et al.  The role of c-myc in cellular growth control , 1999, Oncogene.

[25]  E. Kandel,et al.  Akt/Protein Kinase B Inhibits Cell Death by Preventing the Release of Cytochrome c from Mitochondria , 1999, Molecular and Cellular Biology.

[26]  T. Hunter,et al.  Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  F. Marumo,et al.  Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade. , 1999, Kidney international.

[28]  G. Evan,et al.  The role of c-myc in cell growth. , 1993, Current opinion in genetics & development.

[29]  R. Weinberg,et al.  Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. , 1994, Genes & development.

[30]  Hui Ma,et al.  Chemoattractant‐mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium , 1999, The EMBO journal.

[31]  G. Ruvkun,et al.  The genetics of aging. , 1997, Annual review of genomics and human genetics.

[32]  T. Soderling,et al.  Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway , 1998, Nature.

[33]  L. Pfeffer,et al.  NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase , 1999, Nature.

[34]  J. Woodgett,et al.  PKB/AKT: functional insights from genetic models , 2001, Nature Reviews Molecular Cell Biology.

[35]  G. Ruvkun,et al.  Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. , 1998, Genes & development.

[36]  G M Cohen,et al.  Caspases: the executioners of apoptosis. , 1997, The Biochemical journal.

[37]  K. Seibert,et al.  Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. , 2000, Cancer research.

[38]  Koutarou D. Kimura,et al.  Regulation of C. elegans life-span by insulinlike signaling in the nervous system. , 2000, Science.

[39]  G. Ruvkun Regulation of C.elegans Life Span by Insulin-Like Signaling , 2004 .

[40]  Ji-Hye Kim,et al.  Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway , 2000, Oncogene.

[41]  H. Koh,et al.  Cyclic AMP Inhibits Akt Activity by Blocking the Membrane Localization of PDK1* , 2001, The Journal of Biological Chemistry.

[42]  H. Koh,et al.  Extracellular Zinc Activates p70 S6 Kinase through the Phosphatidylinositol 3-Kinase Signaling Pathway* , 2000, The Journal of Biological Chemistry.

[43]  V. Longo,et al.  Regulation of Longevity and Stress Resistance by Sch9 in Yeast , 2001, Science.

[44]  J. Jorcano,et al.  PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein , 1999, Oncogene.

[45]  M. Scheid,et al.  Role of phosphatidylinositol 3-OH-kinase activity in the inhibition of apoptosis in haemopoietic cells: phosphatidylinositol 3-OH-kinase inhibitors reveal a difference in signalling between interleukin-3 and granulocyte-macrophage colony stimulating factor. , 1995, The Biochemical journal.

[46]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[47]  H. Koh,et al.  Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  Dai Fukumura,et al.  Role of nitric oxide in angiogenesis and microcirculation in tumors , 1998, Cancer and Metastasis Reviews.

[49]  H. Wu,et al.  PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Koh,et al.  Inhibition of Akt and Its Anti-apoptotic Activities by Tumor Necrosis Factor-induced Protein Kinase C-related Kinase 2 (PRK2) Cleavage* , 2000, The Journal of Biological Chemistry.

[51]  R. Schwartz,et al.  Insulin-like Growth Factor-I Extends in VitroReplicative Life Span of Skeletal Muscle Satellite Cells by Enhancing G1/S Cell Cycle Progression via the Activation of Phosphatidylinositol 3′-Kinase/Akt Signaling Pathway* , 2000, The Journal of Biological Chemistry.

[52]  F. McCormick,et al.  Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. , 1997, Science.

[53]  R. Kalb,et al.  Angiopoietin-1 Inhibits Endothelial Cell Apoptosis via the Akt/Survivin Pathway* , 2000, The Journal of Biological Chemistry.

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

[55]  Leslie M Shaw,et al.  Activation of Phosphoinositide 3-OH Kinase by the α6β4 Integrin Promotes Carcinoma Invasion , 1997, Cell.

[56]  S. Ghosh,et al.  Rel/NF-?B and I?B proteins: an overview , 1997 .

[57]  Asim Khwaja,et al.  Matrix adhesion and Ras transformation both activate a phosphoinositide 3‐OH kinase and protein kinase B/Akt cellular survival pathway , 1997, The EMBO journal.

[58]  C. Finch,et al.  Genetics of aging. , 1997, Science.

[59]  M. Takeichi Cadherins in cancer: implications for invasion and metastasis. , 1993, Current opinion in cell biology.

[60]  G. Ruvkun,et al.  A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. , 1999, Genes & development.

[61]  R. Vessella,et al.  Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression* , 2000, The Journal of Biological Chemistry.

[62]  L. Liotta,et al.  Tumor cell interactions with the extracellular matrix during invasion and metastasis. , 1993, Annual review of cell biology.

[63]  G. Ruvkun,et al.  A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans , 1996, Nature.

[64]  T. Jang,et al.  Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. , 2001, Journal of neurosurgery.

[65]  Z. Radisavljevic,et al.  Vascular Endothelial Growth Factor Up-regulates ICAM-1 Expression via the Phosphatidylinositol 3 OH-kinase/AKT/Nitric Oxide Pathway and Modulates Migration of Brain Microvascular Endothelial Cells* , 2000, The Journal of Biological Chemistry.

[66]  W. Sessa,et al.  Regulation of endothelium-derived nitric oxide production by the protein kinase Akt , 1999, Nature.

[67]  N. Rosen,et al.  Cyclin D Expression Is Controlled Post-transcriptionally via a Phosphatidylinositol 3-Kinase/Akt-dependent Pathway* , 1998, The Journal of Biological Chemistry.

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

[69]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[70]  R. Alexander,et al.  Reactive Oxygen Species Mediate the Activation of Akt/Protein Kinase B by Angiotensin II in Vascular Smooth Muscle Cells* , 1999, The Journal of Biological Chemistry.

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

[72]  J. Romashkova,et al.  NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. , 1999, Nature.

[73]  J. Kim,et al.  Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway. , 2000, Circulation research.

[74]  M. Adamo,et al.  Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1* , 2001, The Journal of Biological Chemistry.

[75]  M. Hung,et al.  Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells , 2001, Nature Cell Biology.

[76]  A. Cuadrado,et al.  Activation of Akt/Protein Kinase B by G Protein-coupled Receptors , 1998, The Journal of Biological Chemistry.

[77]  P. Cohen,et al.  Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase‐1 and p70 S6 kinase , 1996, FEBS letters.

[78]  D. Vertommen,et al.  Phosphorylation and Activation of Heart 6-Phosphofructo-2-kinase by Protein Kinase B and Other Protein Kinases of the Insulin Signaling Cascades* , 1997, The Journal of Biological Chemistry.

[79]  R. Weichselbaum,et al.  Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Vishva Dixit,et al.  Vascular Endothelial Growth Factor Regulates Endothelial Cell Survival through the Phosphatidylinositol 3′-Kinase/Akt Signal Transduction Pathway , 1998, The Journal of Biological Chemistry.

[81]  L. Cantley,et al.  The colony stimulating factor-1 receptor associates with and activates phosphatidylinositol-3 kinase , 1989, Nature.

[82]  C. Der,et al.  Ras and Rho regulation of the cell cycle and oncogenesis. , 2001, Cancer letters.

[83]  A. Zeiher,et al.  Phosphorylation of the endothelial nitric oxide synthase at Ser‐1177 is required for VEGF‐induced endothelial cell migration , 2000, FEBS letters.

[84]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[85]  J. Cheng,et al.  Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas , 1995, International journal of cancer.

[86]  A. Zeiher,et al.  Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. , 1998, Circulation research.

[87]  K. Kaestner,et al.  Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). , 2001, Science.

[88]  R. Gottlieb Mitochondria: execution central , 2000, FEBS letters.

[89]  L. Cantley,et al.  Phosphoinositide kinases. , 1998, Annual review of biochemistry.

[90]  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.

[91]  Richard A. Roth,et al.  Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1* , 1999, The Journal of Biological Chemistry.

[92]  J. Woodgett,et al.  Genetic analysis of protein kinase B (AKT) in Drosophila , 1998, Current Biology.

[93]  C. Der,et al.  Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K , 1997, Nature.

[94]  L. Mayo,et al.  A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Hong Sun,et al.  PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[96]  S. Reed,et al.  Different roles for cyclins D1 and E in regulation of the G1-to-S transition , 1995, Molecular and cellular biology.