The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

[1]  L. G. Koss,et al.  Cervical Cancer , 1981, Current Topics in Pathology.

[2]  L. Cantley,et al.  Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. , 1997, Science.

[3]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[4]  T. Hansen,et al.  Identification of a Common Amino Acid Polymorphism in the p85α Regulatory Subunit of Phosphatidylinositol 3-Kinase: Effects on Glucose Disappearance Constant, Glucose Effectiveness, and the Insulin Sensitivity Index , 1997, Diabetes.

[5]  Ajay N. Jain,et al.  Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. , 2002, Cancer research.

[6]  Kap-Seok Yang,et al.  Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Ptak,et al.  Colorectal cancer: Mutations in a signalling pathway , 2005, Nature.

[8]  G. Shulman Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. , 2004, Physiology.

[9]  S. Emr,et al.  Phosphoinositide signaling and the regulation of membrane trafficking in yeast. , 2000, Trends in biochemical sciences.

[10]  S. Emr,et al.  A membrane‐associated complex containing the Vps15 protein kinase and the Vps34 PI 3‐kinase is essential for protein sorting to the yeast lysosome‐like vacuole. , 1993, The EMBO journal.

[11]  L. Cantley,et al.  A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast , 2004, The Journal of cell biology.

[12]  J. Bruce,et al.  Somatic mutations of PTEN in glioblastoma multiforme. , 1997, Cancer research.

[13]  I. Gaidarov,et al.  The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking. , 2001, Molecular cell.

[14]  K. Okkenhaug,et al.  Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. , 2001, Annual review of cell and developmental biology.

[15]  H. Feilotter,et al.  Analysis of PTEN and the 10q23 region in primary prostate carcinomas , 1998, Oncogene.

[16]  R. Parsons Human cancer, PTEN and the PI-3 kinase pathway. , 2004, Seminars in cell & developmental biology.

[17]  J. Blenis,et al.  An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Engelman,et al.  Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice , 2005, Molecular and Cellular Biology.

[19]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[21]  C. Kahn,et al.  Increased P85α Is a Potent Negative Regulator of Skeletal Muscle Insulin Signaling and Induces in Vivo Insulin Resistance Associated with Growth Hormone Excess* , 2005, Journal of Biological Chemistry.

[22]  M. Ittmann,et al.  Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  S. Knuutila,et al.  DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma , 1998, Genes, chromosomes & cancer.

[24]  Wayne A. Phillips,et al.  Mutation of the PIK3CA Gene in Ovarian and Breast Cancer , 2004, Cancer Research.

[25]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[26]  Cristina M. Pinto,et al.  Retracted: Frequent genetic and biochemical alterations of the PI 3‐K/AKT/PTEN pathway in head and neck squamous cell carcinoma , 2005, International journal of cancer.

[27]  J. Friedman,et al.  Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. , 2004, Endocrinology.

[28]  L. Cantley,et al.  Use of RNA Interference-mediated Gene Silencing and Adenoviral Overexpression to Elucidate the Roles of AKT/Protein Kinase B Isoforms in Insulin Actions* , 2003, Journal of Biological Chemistry.

[29]  James T. Murray,et al.  hVps34 Is a Nutrient-regulated Lipid Kinase Required for Activation of p70 S6 Kinase* , 2005, Journal of Biological Chemistry.

[30]  S. Emr,et al.  Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells , 1995, The Journal of cell biology.

[31]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[32]  William R Sellers,et al.  The biology and clinical relevance of the PTEN tumor suppressor pathway. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  P. Finan,et al.  Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy , 2001 .

[34]  O. Cussenot,et al.  PTEN/MMAC1/TEP1 involvement in primary prostate cancers , 1998, Oncogene.

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

[36]  Xin Huang,et al.  Somatic mutation and gain of copy number of PIK3CA in human breast cancer , 2005, Breast Cancer Research.

[37]  J. Backer,et al.  Regulation of the p85/p110alpha phosphatidylinositol 3'-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains. , 1998, The Journal of biological chemistry.

[38]  S. Schwartz,et al.  The prevalence of PIK3CA mutations in gastric and colon cancer. , 2005, European journal of cancer.

[39]  L. S. Harrington,et al.  Restraining PI3K: mTOR signalling goes back to the membrane. , 2005, Trends in biochemical sciences.

[40]  L. Cantley,et al.  Production of novel polyphosphoinositides in vivo is linked to cell transformation by polyomavirus middle T antigen , 1990, Journal of virology.

[41]  C. Kahn,et al.  Regulation of Myocardial Contractility and Cell Size by Distinct PI3K-PTEN Signaling Pathways , 2002, Cell.

[42]  P. Nelson,et al.  Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. , 2003, Cancer cell.

[43]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Hawkins,et al.  The Gβγ Sensitivity of a PI3K Is Dependent upon a Tightly Associated Adaptor, p101 , 1997, Cell.

[45]  L. Guarente,et al.  Genetic pathways that regulate ageing in model organisms , 2000, Nature.

[46]  H. Werner,et al.  The Role of the Insulin‐like Growth Factor‐I Receptor in Cancer , 1995, Annals of the New York Academy of Sciences.

[47]  Roger Davis,et al.  The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 * , 2000, The Journal of Biological Chemistry.

[48]  K. Okkenhaug,et al.  Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation , 2006, Nature.

[49]  S. Emr,et al.  Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy , 2002, The Journal of cell biology.

[50]  P. Kang,et al.  Akt/Protein Kinase B Promotes Organ Growth in Transgenic Mice , 2002, Molecular and Cellular Biology.

[51]  P. Ladenson,et al.  Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. , 2005, The Journal of clinical endocrinology and metabolism.

[52]  Tian Xu,et al.  Akt regulates growth by directly phosphorylating Tsc2 , 2002, Nature Cell Biology.

[53]  B. Stiles,et al.  Insulin Hypersensitivity and Resistance to Streptozotocin-Induced Diabetes in Mice Lacking PTEN in Adipose Tissue , 2005, Molecular and Cellular Biology.

[54]  P. Devreotes,et al.  Chemotaxis: signalling the way forward , 2004, Nature Reviews Molecular Cell Biology.

[55]  C. Kahn,et al.  Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. , 2006, Cell metabolism.

[56]  R. DePinho,et al.  Class IA Phosphoinositide 3-Kinase Regulates Heart Size and Physiological Cardiac Hypertrophy , 2005, Molecular and Cellular Biology.

[57]  J. Tavaré,et al.  The Identification of ATP-citrate Lyase as a Protein Kinase B (Akt) Substrate in Primary Adipocytes* , 2002, The Journal of Biological Chemistry.

[58]  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.

[59]  M. Loda,et al.  The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells , 2005 .

[60]  Christian Hartmann,et al.  PIK3CA mutations in glioblastoma multiforme , 2005, Acta Neuropathologica.

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

[62]  D. Beer,et al.  Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[64]  Inês Barroso,et al.  Candidate Gene Association Study in Type 2 Diabetes Indicates a Role for Genes Involved in β-Cell Function as Well as Insulin Action , 2003, PLoS biology.

[65]  C. Mermel,et al.  ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[66]  E. Hafen,et al.  The Drosophila Forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling , 2003, Journal of biology.

[67]  B. Hemmings,et al.  Physiological functions of protein kinase B/Akt. , 2004, Biochemical Society transactions.

[68]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[69]  C. Kahn,et al.  Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN , 2006, Proceedings of the National Academy of Sciences.

[70]  R. Vessella,et al.  Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[71]  I. Campbell,et al.  The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. , 2001, Cancer research.

[72]  M. Wolter,et al.  Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas , 2000, Virchows Archiv.

[73]  H. Feilotter,et al.  Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma , 1999, British Journal of Cancer.

[74]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[75]  J. Bateman,et al.  Temporal Control of Differentiation by the Insulin Receptor/Tor Pathway in Drosophila , 2004, Cell.

[76]  D. V. van Aalten,et al.  PDK1, the master regulator of AGC kinase signal transduction. , 2004, Seminars in cell & developmental biology.

[77]  H. Just,et al.  Regulation of myocardial contractility and cardiac growth , 1997, Journal of Molecular Medicine.

[78]  J Abbott,et al.  SIGNALLING - THE WAY FORWARD , 2000 .

[79]  F. Natt,et al.  Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[80]  G. Ruvkun,et al.  The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. , 1998, Molecular cell.

[81]  F. Thong,et al.  Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. , 2005, Physiology.

[82]  D. Louis,et al.  PTEN mutations in gliomas and glioneuronal tumors , 1998, Oncogene.

[83]  Wei Zhao,et al.  Mutations of PIK3CA in gastric adenocarcinoma , 2005, BMC Cancer.

[84]  J. Backer,et al.  Regulation of the p85/p110 Phosphatidylinositol 3′-Kinase: Stabilization and Inhibition of the p110α Catalytic Subunit by the p85 Regulatory Subunit , 1998, Molecular and Cellular Biology.

[85]  G. Reifenberger,et al.  Genetic alteration and expression of the phosphoinositol‐3‐kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas , 2005, Neuropathology and applied neurobiology.

[86]  A. Trumpp,et al.  Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the Pten Tumor Suppressor Gene in Vivo , 2001, Science.

[87]  C. James,et al.  PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. , 1997, Cancer research.

[88]  T. Dreyer,et al.  Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma , 2002, The Journal of pathology.

[89]  A. Lash,et al.  Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers , 2005, Clinical Cancer Research.

[90]  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.

[91]  F. Haluska,et al.  Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines , 1998, Oncogene.

[92]  M. Peacocke,et al.  Identification of PTEN mutations in metastatic melanoma specimens , 2000, Journal of medical genetics.

[93]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[94]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[95]  J. A. Hamilton,et al.  Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. , 1998, British Journal of Cancer.

[96]  Dan R. Littman,et al.  PKC-θ knockout mice are protected from fat-induced insulin resistance , 2004 .

[97]  J. Blenis,et al.  PI3-kinase and TOR: PIKTORing cell growth. , 2004, Seminars in cell & developmental biology.

[98]  J. Engelman,et al.  Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. , 2005, Cancer research.

[99]  P. Finan,et al.  Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. , 2003, Biochemical Society transactions.

[100]  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.

[101]  Chi Wai So,et al.  Common mechanism for oncogenic activation of MLL by forkhead family proteins. , 2003, Blood.

[102]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[103]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[104]  D. Dunger,et al.  A Family with Severe Insulin Resistance and Diabetes Due to a Mutation in AKT2 , 2004, Science.

[105]  B. Manning Balancing Akt with S6K , 2004, The Journal of cell biology.

[106]  G. Ruvkun,et al.  Insulin Receptor Substrate and p55 Orthologous Adaptor Proteins Function in the Caenorhabditis elegans daf-2/Insulin-like Signaling Pathway* , 2002, The Journal of Biological Chemistry.

[107]  Takeshi Noda,et al.  Two Distinct Vps34 Phosphatidylinositol 3–Kinase Complexes Function in Autophagy and Carboxypeptidase Y Sorting inSaccharomyces cerevisiae , 2001, The Journal of cell biology.

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

[109]  T. Unterman,et al.  FoxO proteins in insulin action and metabolism , 2005, Trends in Endocrinology & Metabolism.

[110]  T. Mak,et al.  Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease , 2001, Nature Genetics.

[111]  J. Ofrecio,et al.  Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. , 2005, Diabetes.

[112]  P. Pollock,et al.  PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines , 2002, Melanoma research.

[113]  T. Golub,et al.  mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways , 2004, Nature Medicine.

[114]  J. Herman,et al.  Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. , 1997, Cancer research.

[115]  M. Schaefer,et al.  Characterization of p87PIKAP, a Novel Regulatory Subunit of Phosphoinositide 3-Kinase γ That Is Highly Expressed in Heart and Interacts with PDE3B* , 2006, Journal of Biological Chemistry.

[116]  E. Hirsch,et al.  Phosphoinositide 3-kinase γ : kinase-dependent and -independent activities in cardiovascular function and disease , 2004 .

[117]  Hiroyuki Konishi,et al.  The PIK3CA gene is mutated with high frequency in human breast cancers , 2004, Cancer biology & therapy.

[118]  T. Pawson,et al.  SH2 domains recognize specific phosphopeptide sequences , 1993, Cell.

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

[120]  T. Johnson,et al.  A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. , 2002, Genetics.

[121]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[122]  L. Cantley,et al.  Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. , 2006, Cell metabolism.

[123]  D. Leroith,et al.  Insulin and Insulin-Like Growth Factor I Receptors: Similarities and Differences in Signal Transduction , 2004, Hormone Research in Paediatrics.

[124]  R. Medema,et al.  Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty , 2003, Journal of leukocyte biology.

[125]  D. Accili,et al.  FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation , 2004, Cell.

[126]  R. Stein Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. , 2001, Endocrine-related cancer.

[127]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[128]  D. Sabatini,et al.  Growing roles for the mTOR pathway. , 2005, Current opinion in cell biology.

[129]  S R Datta,et al.  14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. , 2000, Molecular cell.

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

[131]  P. Pandolfi,et al.  Impaired Fas response and autoimmunity in Pten+/- mice. , 1999, Science.

[132]  S. Emr,et al.  A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole , 1991, Cell.

[133]  John F. Timms,et al.  Cellular function of phosphoinositide 3-kinases: Implications for development, immunity, homeostasis, and cancer , 2001 .

[134]  P. Hawkins,et al.  p84, a New Gβγ-Activated Regulatory Subunit of the Type IB Phosphoinositide 3-Kinase p110γ , 2005, Current Biology.

[135]  J. Cheng,et al.  Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas , 1998, Molecular carcinogenesis.

[136]  L. Cantley,et al.  Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[137]  A. Meindl,et al.  Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas , 1999, British Journal of Cancer.

[138]  P. Guldberg,et al.  Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. , 2000, The Journal of investigative dermatology.

[139]  Robbie Loewith,et al.  A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling , 2006, Cell.

[140]  T. Sasaki,et al.  T cell-specific loss of Pten leads to defects in central and peripheral tolerance. , 2001, Immunity.

[141]  L. Cantley,et al.  Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation , 1985, Nature.

[142]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.

[143]  Y. Le Marchand-Brustel,et al.  Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. , 2005, Biochimie.

[144]  R. McLendon,et al.  PTEN gene mutations are seen in high-grade but not in low-grade gliomas. , 1997, Cancer research.

[145]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.

[146]  P. Pandolfi,et al.  Pten Dose Dictates Cancer Progression in the Prostate , 2003, PLoS biology.

[147]  S. Staal Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[148]  D. Pot,et al.  A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain , 1997, Molecular and cellular biology.

[149]  E. Hafen,et al.  Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. , 2003, Trends in cell biology.

[150]  Kyucheol Cho,et al.  Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma , 2003, International journal of cancer.

[151]  J. Holik,et al.  Analysis of insulin signalling by RNAi-based gene silencing. , 2004, Biochemical Society transactions.

[152]  J. Blenis,et al.  Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. , 2002, Molecular cell.

[153]  Lewis C Cantley,et al.  Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. , 2005, Genes & development.

[154]  J. Friedman,et al.  Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. , 2004, The Journal of clinical endocrinology and metabolism.

[155]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[156]  Chen-Yang Shen,et al.  PIK3CA as an oncogene in cervical cancer , 2000, Oncogene.

[157]  Suk Woo Nam,et al.  PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas , 2005, Oncogene.

[158]  D. Lambright,et al.  Membrane Recognition and Targeting by Lipid-Binding Domains , 2003, Science's STKE.

[159]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[160]  G. Thomas,et al.  Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. , 2002, Genes & development.

[161]  P. Kang,et al.  The conserved phosphoinositide 3‐kinase pathway determines heart size in mice , 2000, The EMBO journal.

[162]  P. Cohen,et al.  The renaissance of GSK3 , 2001, Nature Reviews Molecular Cell Biology.

[163]  香留 崇 Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions , 2004 .

[164]  P. Kang,et al.  The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway* , 2004, Journal of Biological Chemistry.

[165]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[166]  G. Finocchiaro,et al.  PTEN/MMAC1 mutations in primary glioblastomas and short-term cultures of malignant gliomas , 1998, Oncogene.

[167]  C. Kahn,et al.  Critical nodes in signalling pathways: insights into insulin action , 2006, Nature Reviews Molecular Cell Biology.

[168]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[169]  Johan Auwerx,et al.  Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity , 2004, Nature.

[170]  H. Kaneto,et al.  Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide , 2004, Nature Medicine.