PI3-kinase and TOR: PIKTORing cell growth.

Regulation of growth and proliferation in higher eukaryotic cells results from an integration of nutritional, energy, and mitogenic signals. Biochemical processes underlying cell growth and proliferation are governed by the phosphatidylinositol 3-kinase (PI3K) and target of rapamycin (TOR) signaling pathways. The importance of the interplay between these two pathways is underscored by the discovery that the TOR inhibitor rapamycin is effective against tumors caused by misregulation of the PI3K pathway. We review here recent data concerning the convergence of the PI3K and TOR pathways, the role of these pathways in cell growth and proliferation, and the regulation of growth by downstream TOR targets.

[1]  E. Hafen,et al.  Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. , 2003, Molecular cell.

[2]  Jérôme Boudeau,et al.  Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade , 2003, Journal of biology.

[3]  G. Kellett,et al.  Intestinal Sugar Absorption Is Regulated by Phosphorylation and Turnover of Protein Kinase C βII Mediated by Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Pathways* , 2003, Journal of Biological Chemistry.

[4]  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.

[5]  G. Thomas,et al.  Insulin Signaling: Lessons from the Drosophila Tuberous Sclerosis Complex, a Tumor Suppressor , 2001, Science's STKE.

[6]  M. Mclaughlin,et al.  Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity , 1993, Molecular and cellular biology.

[7]  J. Avruch,et al.  Atypical protein kinase Clambda binds and regulates p70 S6 kinase. , 1998, The Biochemical journal.

[8]  M. Stratton,et al.  A serine/threonine kinase gene defective in Peutz–Jeghers syndrome , 1998, Nature.

[9]  J. Nezu,et al.  Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. , 1998, Nature genetics.

[10]  J. Blenis,et al.  Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb , 2003, Current Biology.

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

[12]  G. Thomas,et al.  The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases , 1996, Molecular and cellular biology.

[13]  J. Blenis,et al.  Regulation of Ribosomal S6 Kinase 2 by Effectors of the Phosphoinositide 3-Kinase Pathway* , 2001, The Journal of Biological Chemistry.

[14]  Hongbing Zhang,et al.  Tsc2 Null Murine Neuroepithelial Cells Are a Model for Human Tuber Giant Cells, and Show Activation of an mTOR Pathway , 2002, Molecular and Cellular Neuroscience.

[15]  P. Vogt,et al.  A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. P. Neufeld,et al.  Erratum: Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adaptor - (Current biology (1999) 9 (1019-1029)) , 1999 .

[17]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

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

[19]  Jie Chen,et al.  Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling , 2001, Science.

[20]  Paul Tempst,et al.  GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. , 2003, Molecular cell.

[21]  Brian A. Hemmings,et al.  Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation , 1999, Molecular and Cellular Biology.

[22]  A. Meijer,et al.  Phosphorylation of Ribosomal Protein S6 Is Inhibitory for Autophagy in Isolated Rat Hepatocytes (*) , 1995, The Journal of Biological Chemistry.

[23]  E. Hafen,et al.  Drosophila S6 kinase: a regulator of cell size. , 1999, Science.

[24]  David J. Kwiatkowski,et al.  Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Takeshi Noda,et al.  Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast* , 1998, The Journal of Biological Chemistry.

[26]  O. Hino,et al.  Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling , 2002, Nature Cell Biology.

[27]  Benno J. Rensing,et al.  Sustained Suppression of Neointimal Proliferation by Sirolimus-Eluting Stents: One-Year Angiographic and Intravascular Ultrasound Follow-Up , 2001, Circulation.

[28]  G C Johnston,et al.  Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. , 1977, Experimental cell research.

[29]  N. Sonenberg,et al.  Signaling from Akt to FRAP/TOR Targets both 4E-BP andS6K in Drosophilamelanogaster , 2003, Molecular and Cellular Biology.

[30]  J. Avruch,et al.  Multiple independent inputs are required for activation of the p70 S6 kinase , 1995, Molecular and cellular biology.

[31]  A. Jaeschke,et al.  Mammalian TOR: A Homeostatic ATP Sensor , 2001, Science.

[32]  繁光 薫 Structural requirement of leucine for activation of p70 S6 kinase , 1999 .

[33]  C. Rommel,et al.  Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways , 2001, Nature Cell Biology.

[34]  G. Mills,et al.  Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. Dickson,et al.  The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation , 2001, Cell.

[36]  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.

[37]  C. Potter,et al.  Drosophila Tsc1 Functions with Tsc2 to Antagonize Insulin Signaling in Regulating Cell Growth, Cell Proliferation, and Organ Size , 2001, Cell.

[38]  M. Andjelkovic,et al.  Phosphorylation and activation of p70s6k by PDK1. , 1998, Science.

[39]  P. Serruys,et al.  A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. , 2002, The New England journal of medicine.

[40]  N. Sonenberg,et al.  Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap , 1990, Nature.

[41]  M. Kozak Structural features in eukaryotic mRNAs that modulate the initiation of translation. , 1991, The Journal of biological chemistry.

[42]  S. Schreiber,et al.  Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Christine C. Hudson,et al.  Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin , 2002, Molecular and Cellular Biology.

[44]  Dario R. Alessi,et al.  3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro , 1998, Current Biology.

[45]  David Carling,et al.  Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Tobias Schmelzle,et al.  TOR, a Central Controller of Cell Growth , 2000, Cell.

[47]  G. Thomas,et al.  Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  W. J. Wu,et al.  Cdc42 Stimulates RNA Splicing via the S6 Kinase and a Novel S6 Kinase Target, the Nuclear Cap-binding Complex* , 2000, The Journal of Biological Chemistry.

[49]  F. Tamanoi,et al.  Drosophila Rheb GTPase is required for cell cycle progression and cell growth , 2003, Journal of Cell Science.

[50]  N. Sonenberg,et al.  The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila , 2001, Nature Cell Biology.

[51]  T. Golub,et al.  The Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation , 2002, Molecular and Cellular Biology.

[52]  C. Proud,et al.  Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase , 2001, The EMBO journal.

[53]  Christine C. Hudson,et al.  A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. , 2000, Cancer research.

[54]  J. Kunz,et al.  Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression , 1993, Cell.

[55]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[56]  M. Mann,et al.  p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  R. Snell,et al.  Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. , 1998, Human molecular genetics.

[58]  Hongbing Zhang,et al.  A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. , 2002, Human molecular genetics.

[59]  D. Goberdhan,et al.  Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. , 1999, Genes & development.

[60]  A. Gingras,et al.  The mRNA 5' cap-binding protein eIF4E and control of cell growth. , 1998, Current opinion in cell biology.

[61]  J. Blenis,et al.  Inactivation of the Tuberous Sclerosis Complex-1 and -2 Gene Products Occurs by Phosphoinositide 3-Kinase/Akt-dependent and -independent Phosphorylation of Tuberin* , 2003, Journal of Biological Chemistry.

[62]  J. Blenis,et al.  p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex , 1999, Molecular and Cellular Biology.

[63]  E. Gelfand,et al.  Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  A. Gingras,et al.  Regulation of translation initiation by FRAP/mTOR. , 2001, Genes & development.

[65]  J. Blenis,et al.  Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. , 2002, Genes & development.

[66]  R. Garofalo,et al.  The Drosophila insulin receptor is required for normal growth. , 1996, Endocrinology.

[67]  B. Edgar,et al.  Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins , 2003, Nature Cell Biology.

[68]  Jennifer Skeen,et al.  Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. , 2003, Genes & development.

[69]  J. Blenis,et al.  mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E , 2004, Molecular and Cellular Biology.

[70]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[71]  Lewis C Cantley,et al.  The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[72]  J. Avruch,et al.  Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action , 2002, Cell.

[73]  A. Schmidt,et al.  Starvation Induces Vacuolar Targeting and Degradation of the Tryptophan Permease in Yeast , 1999, The Journal of cell biology.

[74]  A. Gingras,et al.  eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. , 1999, Annual review of biochemistry.

[75]  J. Blenis,et al.  Structural and functional analysis of pp70S6k. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[76]  M. Vigneron,et al.  Control of Nutrient-Sensitive Transcription Programs by the Unconventional Prefoldin URI , 2003, Science.

[77]  P. Sassone-Corsi,et al.  Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: An alternative route to mitogen-induced gene expression , 1994, Cell.

[78]  E. Hafen,et al.  Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4 , 1999, Cell.

[79]  I. Stansfield,et al.  An MBoC Favorite: TOR controls translation initiation and early G1 progression in yeast , 2012, Molecular biology of the cell.

[80]  J. Blenis,et al.  Identification of a Conserved Motif Required for mTOR Signaling , 2002, Current Biology.

[81]  Hua Tang,et al.  Amino Acid-Induced Translation of TOP mRNAs Is Fully Dependent on Phosphatidylinositol 3-Kinase-Mediated Signaling, Is Partially Inhibited by Rapamycin, and Is Independent of S6K1 and rpS6 Phosphorylation , 2001, Molecular and Cellular Biology.

[82]  A. Git,et al.  The Expression of Poly(A)-binding Protein Gene Is Translationally Regulated in a Growth-dependent Fashion through a 5′-Terminal Oligopyrimidine Tract Motif* , 1999, The Journal of Biological Chemistry.

[83]  David Carling,et al.  Supplemental Data LKB 1 Is the Upstream Kinase in the AMP-Activated Protein Kinase Cascade , 2003 .

[84]  J. Avruch,et al.  Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism* , 1998, The Journal of Biological Chemistry.

[85]  RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[87]  B. Edgar,et al.  The Drosophila Cyclin D–Cdk4 complex promotes cellular growth , 2000, The EMBO journal.

[88]  C. Tsang,et al.  Chromatin‐mediated regulation of nucleolar structure and RNA Pol I localization by TOR , 2003, The EMBO journal.

[89]  K. Inoki,et al.  Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. , 2003, Genes & development.

[90]  D. Hardie,et al.  AMP‐activated protein kinase: the energy charge hypothesis revisited , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

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

[92]  J. Blenis,et al.  TOS Motif-Mediated Raptor Binding Regulates 4E-BP1 Multisite Phosphorylation and Function , 2003, Current Biology.

[93]  C. Proud,et al.  Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. , 2003, The Biochemical journal.

[94]  D. Alessi,et al.  Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. , 2003, The Biochemical journal.

[95]  A. Schmidt,et al.  The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease , 1998, The EMBO journal.

[96]  M. Hall,et al.  TOR2 is required for organization of the actin cytoskeleton in yeast. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[97]  J. Heitman,et al.  The TOR Kinases Link Nutrient Sensing to Cell Growth* , 2001, The Journal of Biological Chemistry.

[98]  V. M. Pain,et al.  A Reevaluation of the Cap-binding Protein, eIF4E, as a Rate-limiting Factor for Initiation of Translation in Reticulocyte Lysate (*) , 1996, The Journal of Biological Chemistry.

[99]  D. Sabatini,et al.  mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery , 2002, Cell.

[100]  Xinsheng Gao,et al.  TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. , 2001, Genes & development.

[101]  J. Celis,et al.  Distinct repression of translation by wortmannin and rapamycin. , 1997, European journal of biochemistry.

[102]  J. Montagne,et al.  A Nutrient Sensor Mechanism Controls Drosophila Growth , 2003, Cell.

[103]  T. P. Neufeld,et al.  Coordination of Growth and Cell Division in the Drosophila Wing , 1998, Cell.

[104]  B. Edgar,et al.  Rheb promotes cell growth as a component of the insulin/TOR signalling network , 2003, Nature Cell Biology.

[105]  T. Powers,et al.  Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. , 1999, Molecular biology of the cell.

[106]  J. Blenis,et al.  Characterization of Phosphatidylinositol 3-Kinase-dependent Phosphorylation of the Hydrophobic Motif Site Thr389 in p70 S6 Kinase 1* , 2002, The Journal of Biological Chemistry.

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

[108]  R. Roth,et al.  Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. , 2003, American journal of physiology. Endocrinology and metabolism.

[109]  R. Pearson,et al.  mTOR-Dependent Regulation of Ribosomal Gene Transcription Requires S6K1 and Is Mediated by Phosphorylation of the Carboxy-Terminal Activation Domain of the Nucleolar Transcription Factor UBF† , 2003, Molecular and Cellular Biology.

[110]  A. Carrera,et al.  Phosphoinositide 3-Kinase Activation Regulates Cell Division Time by Coordinated Control of Cell Mass and Cell Cycle Progression Rate* , 2003, Journal of Biological Chemistry.

[111]  S. Nicosia,et al.  Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Tuberous Sclerosis Tumor Suppressor Complex by Phosphorylation of Tuberin* , 2002, The Journal of Biological Chemistry.

[112]  C. Thompson,et al.  Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. , 2002, Molecular biology of the cell.

[113]  J. Blenis,et al.  Ribosomal S6 Kinase 2 Inhibition by a Potent C-terminal Repressor Domain Is Relieved by Mitogen-activated Protein-Extracellular Signal-regulated Kinase Kinase-regulated Phosphorylation* , 2001, The Journal of Biological Chemistry.

[114]  E. Hafen,et al.  PDK1 regulates growth through Akt and S6K in Drosophila , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[115]  木村 直樹 A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway , 2003 .

[116]  N. Socci,et al.  Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. , 2003, Molecular cell.

[117]  Lewis C. Cantley,et al.  The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function* , 1999, The Journal of Biological Chemistry.

[118]  D. Kwiatkowski,et al.  Tuberous Sclerosis: from Tubers to mTOR , 2003, Annals of human genetics.

[119]  G. Landreth,et al.  S6 phosphorylation-independent pathways regulate translation of 5'-terminal oligopyrimidine tract-containing mRNAs in differentiating hematopoietic cells. , 2002, Nucleic acids research.

[120]  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.

[121]  D. Kwiatkowski,et al.  Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation , 2002, The Journal of Biological Chemistry.

[122]  J. Crespo,et al.  Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. , 2002, Molecular cell.

[123]  Hua Tang,et al.  Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation , 2002, Molecular and Cellular Biology.

[124]  M. Chou,et al.  Atypical Protein Kinases Cλ and -ζ Associate with the GTP-Binding Protein Cdc42 and Mediate Stress Fiber Loss , 2000, Molecular and Cellular Biology.

[125]  A. Nairn,et al.  Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[126]  R. Abraham,et al.  Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells (*) , 1995, The Journal of Biological Chemistry.

[127]  J. Heitman,et al.  The TOR signaling cascade regulates gene expression in response to nutrients. , 1999, Genes & development.

[128]  E. Hafen,et al.  Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. , 2000, Genes & development.

[129]  P. Cohen,et al.  The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells , 2000, Current Biology.

[130]  D. Alessi,et al.  Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. , 1999, The Biochemical journal.

[131]  R. Pearson,et al.  Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k , 1997, The EMBO journal.

[132]  S. Sehgal Sirolimus: its discovery, biological properties, and mechanism of action. , 2003, Transplantation proceedings.

[133]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[134]  A. Gingras,et al.  Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. , 1999, Molecular cell.

[135]  J. Blenis,et al.  Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. , 2002, Advances in cancer research.

[136]  T. P. Neufeld,et al.  Regulation of cellular growth by the Drosophila target of rapamycin dTOR. , 2000, Genes & development.

[137]  A. F. Castro,et al.  Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner* , 2003, Journal of Biological Chemistry.

[138]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[139]  Stefano Fumagalli,et al.  Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase , 1998, The EMBO journal.

[140]  E. Hafen,et al.  Rheb is an essential regulator of S6K in controlling cell growth in Drosophila , 2003, Nature Cell Biology.

[141]  J. Avruch,et al.  The Mammalian Target of Rapamycin (mTOR) Partner, Raptor, Binds the mTOR Substrates p70 S6 Kinase and 4E-BP1 through Their TOR Signaling (TOS) Motif* , 2003, The Journal of Biological Chemistry.

[142]  Stuart L. Schreiber,et al.  Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins , 2000, Current Biology.

[143]  Paul Tempst,et al.  RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs , 1994, Cell.