mTOR: a pharmacologic target for autophagy regulation.

mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism. mTOR regulates cell growth and proliferation in response to a wide range of cues, and its signaling pathway is deregulated in many human diseases. mTOR also plays a crucial role in regulating autophagy. This Review provides an overview of the mTOR signaling pathway, the mechanisms of mTOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment.

[1]  P. Codogno,et al.  Development of autophagy inducers in clinical medicine. , 2015, The Journal of clinical investigation.

[2]  Junying Yuan,et al.  Pharmacologic agents targeting autophagy. , 2015, The Journal of clinical investigation.

[3]  K. Guan,et al.  Rag GTPases are cardioprotective by regulating lysosomal function , 2014, Nature Communications.

[4]  D. Sabatini,et al.  Regulation of mTORC1 by amino acids. , 2014, Trends in cell biology.

[5]  Dudley Lamming,et al.  RagA, but not RagB, is essential for embryonic development and adult mice. , 2014, Developmental cell.

[6]  Sang Gyun Kim,et al.  Rapamycin: one drug, many effects. , 2014, Cell metabolism.

[7]  Michael N. Hall,et al.  Making new contacts: the mTOR network in metabolism and signalling crosstalk , 2014, Nature Reviews Molecular Cell Biology.

[8]  L. Cantley,et al.  Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome , 2014, Cell.

[9]  W. Lin,et al.  Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling , 2014, Cell Death and Disease.

[10]  Kun-Liang Guan,et al.  Autophagy regulation by nutrient signaling , 2013, Cell Research.

[11]  C. Hetz,et al.  Measurement of autophagy flux in the nervous system in vivo , 2013, Cell Death and Disease.

[12]  D. Sabatini,et al.  The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. , 2013, Molecular cell.

[13]  K. Guan,et al.  Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy , 2013, Autophagy.

[14]  M. Hall,et al.  Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells , 2013, Cell.

[15]  S. Y. Kim,et al.  Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence , 2013, Autophagy.

[16]  D. Sabatini,et al.  mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin , 2013, Science.

[17]  Andrea Ballabio,et al.  Signals from the lysosome: a control centre for cellular clearance and energy metabolism , 2013, Nature Reviews Molecular Cell Biology.

[18]  D. Sabatini,et al.  Regulation of mTORC1 and its impact on gene expression at a glance , 2013, Journal of Cell Science.

[19]  Matthew Meyerson,et al.  A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 , 2013, Science.

[20]  Mauro Piacentini,et al.  mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6 , 2013, Nature Cell Biology.

[21]  Lan Ye,et al.  Rapalogs and mTOR inhibitors as anti-aging therapeutics. , 2013, The Journal of clinical investigation.

[22]  J. Martina,et al.  Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes , 2013, The Journal of cell biology.

[23]  K. Guan,et al.  Amino acid signalling upstream of mTOR , 2013, Nature Reviews Molecular Cell Biology.

[24]  K. Guan,et al.  Differential Regulation of Distinct Vps34 Complexes by AMPK in Nutrient Stress and Autophagy , 2013, Cell.

[25]  D. Sabatini,et al.  Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1 , 2012, Cell.

[26]  D. Rubinsztein,et al.  Autophagy modulation as a potential therapeutic target for diverse diseases , 2012, Nature Reviews Drug Discovery.

[27]  Yong Chen,et al.  MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB , 2012, Autophagy.

[28]  Sunghoon Kim,et al.  Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway , 2012, Cell.

[29]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[30]  D. Xiao,et al.  Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy , 2012, Cell Death and Disease.

[31]  A. Ballabio,et al.  A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB , 2012, The EMBO journal.

[32]  H. Eguchi,et al.  Rapamycin Causes Upregulation of Autophagy and Impairs Islets Function Both In Vitro and In Vivo , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[33]  Masaaki Komatsu,et al.  Autophagy: Renovation of Cells and Tissues , 2011, Cell.

[34]  M. Hall,et al.  Rapamycin passes the torch: a new generation of mTOR inhibitors , 2011, Nature Reviews Drug Discovery.

[35]  Roberto Zoncu,et al.  mTORC1 Senses Lysosomal Amino Acids Through an Inside-Out Mechanism That Requires the Vacuolar H+-ATPase , 2011, Science.

[36]  F. Sinicrope,et al.  Inhibition of mTOR Kinase by AZD8055 Can Antagonize Chemotherapy-induced Cell Death through Autophagy Induction and Down-regulation of p62/Sequestosome 1* , 2011, The Journal of Biological Chemistry.

[37]  P. Bahadoran,et al.  Metformin inhibits melanoma development through autophagy and apoptosis mechanisms , 2011, Cell Death and Disease.

[38]  D. Kwiatkowski,et al.  Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent , 2011, Proceedings of the National Academy of Sciences.

[39]  I. Ben-Sahra,et al.  Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. , 2011, Cancer research.

[40]  Andrea Ballabio,et al.  TFEB Links Autophagy to Lysosomal Biogenesis , 2011, Science.

[41]  S. Gygi,et al.  Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling , 2011, Science.

[42]  M. Zou,et al.  Improvement of Cardiac Functions by Chronic Metformin Treatment Is Associated With Enhanced Cardiac Autophagy in Diabetic OVE26 Mice , 2011, Diabetes.

[43]  Daniel J. Klionsky,et al.  Relieving Autophagy and 4EBP1 from Rapamycin Resistance , 2011, Molecular and Cellular Biology.

[44]  D. Sabatini,et al.  The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling , 2011, Science.

[45]  B. Hennessy,et al.  Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. , 2011, The Journal of clinical investigation.

[46]  W. Oppliger,et al.  Activation of mTORC2 by Association with the Ribosome , 2011, Cell.

[47]  B. Viollet,et al.  AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 , 2011, Nature Cell Biology.

[48]  Philippe P Roux,et al.  mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide , 2010, The EMBO journal.

[49]  D. Guertin,et al.  Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy , 2010, Oncogene.

[50]  B. Viollet,et al.  Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. , 2010, Cell metabolism.

[51]  Tohru Natsume,et al.  Tti1 and Tel2 Are Critical Factors in Mammalian Target of Rapamycin Complex Assembly* , 2010, The Journal of Biological Chemistry.

[52]  D. Hailey,et al.  Autophagy termination and lysosome reformation regulated by mTOR , 2010, Nature.

[53]  Chang Hwa Jung,et al.  mTOR regulation of autophagy , 2010, FEBS letters.

[54]  D. Sabatini,et al.  Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids , 2010, Cell.

[55]  Philippe P Roux,et al.  mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling , 2009, Molecular and Cellular Biology.

[56]  J. Auwerx,et al.  mTOR complex 2 in adipose tissue negatively controls whole-body growth , 2009, Proceedings of the National Academy of Sciences.

[57]  She Chen,et al.  ULK1·ATG13·FIP200 Complex Mediates mTOR Signaling and Is Essential for Autophagy* , 2009, Journal of Biological Chemistry.

[58]  D. Sabatini,et al.  DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival , 2009, Cell.

[59]  D. Guertin,et al.  The Pharmacology of mTOR Inhibition , 2009, Science Signaling.

[60]  C. Jung,et al.  ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. , 2009, Molecular biology of the cell.

[61]  J. Guan,et al.  Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. , 2009, Molecular biology of the cell.

[62]  D. Sabatini,et al.  An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1* , 2009, Journal of Biological Chemistry.

[63]  D. Guertin,et al.  mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. , 2009, Cancer cell.

[64]  Sang Gyun Kim,et al.  Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation , 2008, Proceedings of the National Academy of Sciences.

[65]  T. P. Neufeld,et al.  Regulation of TORC1 by Rag GTPases in nutrient response , 2008, Nature Cell Biology.

[66]  David M. Sabatini,et al.  The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1 , 2008, Science.

[67]  B. Turk,et al.  AMPK phosphorylation of raptor mediates a metabolic checkpoint. , 2008, Molecular cell.

[68]  D. Sgroi,et al.  Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. , 2008, Genes & development.

[69]  D. Hardie.  Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease , 2008, FEBS letters.

[70]  Robin Mathew,et al.  Role of autophagy in cancer , 2007, Nature Reviews Cancer.

[71]  Adiel Cohen,et al.  PRAS40 and PRR5-Like Protein Are New mTOR Interactors that Regulate Apoptosis , 2007, PloS one.

[72]  N. Sonenberg,et al.  Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. , 2007, Cancer research.

[73]  D. Alessi,et al.  Identification of Protor as a novel Rictor-binding component of mTOR complex-2. , 2007, The Biochemical journal.

[74]  B. Viollet,et al.  Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. , 2007, Cancer research.

[75]  R. Roth,et al.  PRAS40 Regulates mTORC1 Kinase Activity by Functioning as a Direct Inhibitor of Substrate Binding* , 2007, Journal of Biological Chemistry.

[76]  S. Carr,et al.  PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. , 2007, Molecular cell.

[77]  Timothy J. Griffin,et al.  Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 , 2007, Nature Cell Biology.

[78]  K. Inoki,et al.  Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. , 2006, Genes & development.

[79]  J. Qin,et al.  SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity , 2006, Cell.

[80]  Jacob D. Jaffe,et al.  mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s , 2006, Current Biology.

[81]  G. Kroemer,et al.  Current development of mTOR inhibitors as anticancer agents , 2006, Nature Reviews Drug Discovery.

[82]  Alexandros Tzatsos,et al.  Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation , 2006, Molecular and Cellular Biology.

[83]  Paul Tempst,et al.  Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis , 2005, Cell.

[84]  G. Mills,et al.  Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. , 2005, Cancer research.

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

[86]  E. Hafen,et al.  Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. , 2004, Genes & development.

[87]  R. Loewith,et al.  Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive , 2004, Nature Cell Biology.

[88]  Steven P Gygi,et al.  Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[90]  T. P. Neufeld,et al.  Role and regulation of starvation-induced autophagy in the Drosophila fat body. , 2004, Developmental cell.

[91]  D. Guertin,et al.  Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton , 2004, Current Biology.

[92]  I. Gout,et al.  The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins , 2004, The Journal of cell biology.

[93]  Francesco Scaravilli,et al.  Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease , 2004, Nature Genetics.

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

[95]  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.

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

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

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

[99]  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.

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

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

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

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

[104]  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.

[105]  Rainer Duden,et al.  Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. , 2002, Human molecular genetics.

[106]  T. Nishimoto,et al.  Novel G Proteins, Rag C and Rag D, Interact with GTP-binding Proteins, Rag A and Rag B* , 2001, The Journal of Biological Chemistry.

[107]  Y. Ohsumi,et al.  Tor-Mediated Induction of Autophagy via an Apg1 Protein Kinase Complex , 2000, The Journal of cell biology.

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

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

[110]  V. Berlin,et al.  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.

[111]  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.

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

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

[114]  C. Schworer,et al.  Induction of autophagy by amino-acid deprivation in perfused rat liver , 1977, Nature.

[115]  W. Bradford,et al.  Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. , 1976, The American journal of pathology.

[116]  S. L. Clark.  CELLULAR DIFFERENTIATION IN THE KIDNEYS OF NEWBORN MICE STUDIED WITH THE ELECTRON MICROSCOPE , 1957, The Journal of biophysical and biochemical cytology.

[117]  S. Ryter,et al.  Autophagy in human health and disease. , 2013, The New England journal of medicine.

[118]  Lisa L. Smith,et al.  AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. , 2010, Cancer research.

[119]  C. Duve,et al.  Functions of lysosomes. , 1966, Annual review of physiology.