mTOR at the nexus of nutrition, growth, ageing and disease


The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Structure and function of mTORC1 and mTORC2.
Fig. 2: Targets of mTORC1 and mTORC2 signalling.
Fig. 3: Upstream regulators of the mTOR signalling pathway.
Fig. 4: mTOR signalling in metabolism.
Fig. 5: mTOR signalling in the brain.
Fig. 6: mTOR in cancer and ageing.

Change history

  • 31 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  1. 1.

    Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726 (1975).

  2. 2.

    Martel, R. R., Klicius, J. & Galet, S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J. Physiol. Pharmacol. 55, 48–51 (1977).

  3. 3.

    Eng, C. P., Sehgal, S. N. & Vezina, C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. 37, 1231–1237 (1984).

  4. 4.

    Houchens, D. P., Ovejera, A. A., Riblet, S. M. & Slagel, D. E. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur. J. Cancer Clin. Oncol. 19, 799–805 (1983).

  5. 5.

    Bierer, B. E. et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc. Natl Acad. Sci. USA 87, 9231–9235 (1990).

  6. 6.

    Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Rapamycin–FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227–1236 (1992).

  7. 7.

    Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin–receptor complex. Nature 369, 756–758 (1994).

  8. 8.

    Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

  9. 9.

    Sabers, C. J. et al. Isolation of a protein target of the FKBP12–rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822 (1995).

  10. 10.

    Heitman, J., Movva, N. R. & Hall, M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).

  11. 11.

    Cafferkey, R. et al. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell Biol. 13, 6012–6023 (1993).

  12. 12.

    Kunz, J. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596 (1993).

  13. 13.

    Helliwell, S. B. et al. TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol. Biol. Cell 5, 105–118 (1994).

  14. 14.

    Keith, C. T. & Schreiber, S. L. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270, 50 (1995).

  15. 15.

    Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003).

  16. 16.

    Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

  17. 17.

    Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).

  18. 18.

    Yang, H. et al. mTOR kinase structure, mechanism and regulation. Nature 497, 217–223 (2013).

  19. 19.

    Guertin, D. A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).

  20. 20.

    Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797–806 (2003).

  21. 21.

    Nojima, H. 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. J. Biol. Chem. 278, 15461–15464 (2003).

  22. 22.

    Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915 (2007).

  23. 23.

    Vander Haar, E., Lee, S.-I., Bandhakavi, S., Griffin, T. J. & Kim, D.-H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323 (2007).

  24. 24.

    Peterson, T. R. et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886 (2009).

  25. 25.

    Yip, C. K., Murata, K., Walz, T., Sabatini, D. M. & Kang, S. A. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38, 768–774 (2010).

  26. 26.

    Aylett, C. H. et al. Architecture of human mTOR complex 1. Science 351, 48–52 (2016).

  27. 27.

    Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373 (2017).

  28. 28.

    Hwang, Y. et al. Disruption of the scaffolding function of mLST8 selectively inhibits mTORC2 assembly and function and suppresses mTORC2-dependent tumor growth in vivo. Cancer Res. 79, 3178 (2019).

  29. 29.

    Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

  30. 30.

    Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128 (2004).

  31. 31.

    Frias, M. A. et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865–1870 (2006).

  32. 32.

    Jacinto, E. et al. SIN1/MIP1 maintains rictor–mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125–137 (2006).

  33. 33.

    Yang, Q., Inoki, K., Ikenoue, T. & Guan, K. L. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820–2832 (2006).

  34. 34.

    Pearce, L. R. et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405, 513–522 (2007).

  35. 35.

    Woo, S. Y. et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor β expression and signaling. J. Biol. Chem. 282, 25604–25612 (2007).

  36. 36.

    Yuan, H.-X. & Guan, K.-L. The SIN1-PH domain connects mTORC2 to PI3K. Cancer Discov. 5, 1127–1129 (2015). This study shows that PIP3 activates mTORC2 by binding the pleckstrin homology domain of mSin1, which otherwise autoinhibits the kinase.

  37. 37.

    Chen, X. et al. Cryo-EM structure of human mTOR complex 2. Cell Res. 28, 518–528 (2018).

  38. 38.

    Stuttfeld, E. et al. Architecture of the human mTORC2 core complex. eLife 7, e33101 (2018).

  39. 39.

    Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

  40. 40.

    Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).

  41. 41.

    Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).

  42. 42.

    Kang, S. A. et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341, 1236566 (2013).

  43. 43.

    Choo, A. Y., Yoon, S.-O., Kim, S. G., Roux, P. P. & Blenis, J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA 105, 17414–17419 (2008).

  44. 44.

    Buttgereit, F. & Brand, M. D. A hierarchy of ATP-consuming processes in mammalian cells. Biochem. J. 312, 163–167 (1995).

  45. 45.

    Brunn, G. J. et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99–101 (1997).

  46. 46.

    Gingras, A. C. et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13, 1422–1437 (1999).

  47. 47.

    Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).

  48. 48.

    Pullen, N. et al. Phosphorylation and activation of p70s6k by PDK1. Science 279, 707 (1998).

  49. 49.

    Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H. & Sabatini, D. M. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA 95, 1432–1437 (1998).

  50. 50.

    Ruvinsky, I. et al. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 19, 2199–2211 (2005). This study reports that a mouse bearing serine to alanine substitutions at all five phosphorylatable serines in ribosomal protein S6 does not experience any global defects in translation.

  51. 51.

    Chauvin, C. et al. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474 (2013).

  52. 52.

    Hannan, K. M. 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. Mol. Cell Biol. 23, 8862–8877 (2003).

  53. 53.

    Mayer, C., Zhao, J., Yuan, X. & Grummt, I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 18, 423–434 (2004).

  54. 54.

    Michels, A. A. et al. mTORC1 directly phosphorylates and regulates human MAF1. Mol. Cell Biol. 30, 3749 (2010).

  55. 55.

    Shor, B. et al. Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells. J. Biol. Chem. 285, 15380–15392 (2010).

  56. 56.

    Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569–580 (2005).

  57. 57.

    Dorrello, N. V. et al. S6K1- and βTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314, 467–471 (2006).

  58. 58.

    Ma, X. M., Yoon, S. O., Richardson, C. J., Julich, K. & Blenis, J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133, 303–313 (2008).

  59. 59.

    Mieulet, V. et al. S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover. Am. J. Physiol. Cell Physiol. 293, C712–C722 (2007).

  60. 60.

    Pende, M. et al. S6K1–/–/S6K2–/– mice exhibit perinatal lethality and rapamycin-sensitive 5ʹ-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell Biol. 24, 3112–3124 (2004).

  61. 61.

    Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55 (2012).

  62. 62.

    Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

  63. 63.

    Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

  64. 64.

    Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011).

  65. 65.

    Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

  66. 66.

    Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010). Using transcriptional and metabolic profiling, this study demonstrates that mTORC1 activates HIF1α and the SREBPs to induce glycolysis, lipid synthesis and the pentose phosphate pathway.

  67. 67.

    Kim, J. E. & Chen, J. Regulation of peroxisome proliferator-activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53, 2748–2756 (2004).

  68. 68.

    Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016).

  69. 69.

    Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013).

  70. 70.

    Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013).

  71. 71.

    Valvezan, A. J. et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell 32, 624–638 (2017).

  72. 72.

    He, L. et al. mTORC1 promotes metabolic reprogramming by the suppression of GSK3-dependent Foxk1 phosphorylation. Mol. Cell 70, 949–960 (2018).

  73. 73.

    Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009).

  74. 74.

    Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex. Nature 450, 736–740 (2007).

  75. 75.

    Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

  76. 76.

    Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009). Together with Kim et al. (2011), this study shows that mTORC1 directly regulates initiation of autophagy by applying inhibitory phosphorylations to components of the ULK1 complex.

  77. 77.

    Ganley, I. G. et al. ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297–12305 (2009).

  78. 78.

    Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

  79. 79.

    Kim, Y. M. et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol. Cell 57, 207–218 (2015).

  80. 80.

    Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

  81. 81.

    Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

  82. 82.

    Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).

  83. 83.

    Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942 (2010).

  84. 84.

    Odle, R. I. et al. An mTORC1-to-CDK1 switch maintains autophagy suppression during mitosis. Mol Cell, (2019).

  85. 85.

    Wyant, G. A. et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell 171, 642–654 (2017).

  86. 86.

    Wyant, G. A. et al. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 360, 751–758 (2018).

  87. 87.

    Guo, J. Y. et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 30, 1704–1717 (2016).

  88. 88.

    Kraft, C., Deplazes, A., Sohrmann, M. & Peter, M. Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat. Cell Biol. 10, 602–610 (2008).

  89. 89.

    An, H. & Harper, J. W. Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy. Nat. Cell Biol. 20, 135–143 (2018).

  90. 90.

    Larsson, C. Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal. 18, 276–284 (2006).

  91. 91.

    Liu, L., Das, S., Losert, W. & Parent, C. A. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19, 845–857 (2010).

  92. 92.

    Schmidt, K. M. et al. Inhibition of mTORC2/RICTOR impairs melanoma hepatic metastasis. Neoplasia 20, 1198–1208 (2018).

  93. 93.

    Morrison Joly, M. et al. Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis. Breast Cancer Res. 19, 74 (2017).

  94. 94.

    Ikenoue, T., Inoki, K., Yang, Q., Zhou, X. & Guan, K. L. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919–1931 (2008).

  95. 95.

    Li, X. & Gao, T. mTORC2 phosphorylates protein kinase Cζ to regulate its stability and activity. EMBO Rep. 15, 191–198 (2014).

  96. 96.

    García-Martínez, Juan M. & Alessi, DarioR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416, 375 (2008).

  97. 97.

    Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307, 1098–1101 (2005).

  98. 98.

    Webb, A. E. & Brunet, A. FOXO transcription factors: key regulators of cellular quality control. Trends Biochem. Sci. 39, 159–169 (2014).

  99. 99.

    Hoxhaj, G. et al. Direct stimulation of NADP+ synthesis through Akt-mediated phosphorylation of NAD kinase. Science 363, 1088–1092 (2019).

  100. 100.

    Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).

  101. 101.

    Humphrey, S. J. et al. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab. 17, 1009–1020 (2013).

  102. 102.

    Ebner, M., Sinkovics, B., Szczygieł, M., Ribeiro, D. W. & Yudushkin, I. Localization of mTORC2 activity inside cells. J. Cell Biol. 216, 343 (2017).

  103. 103.

    Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

  104. 104.

    Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713 (2005).

  105. 105.

    Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).

  106. 106.

    Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008). Together with Sancak et al. (2008), this study defines the Rag-GTPases as a second upstream signalling branch that transduces amino acid availability to mTORC1. Sancak et al.’s study also shows that mTORC1 localizes to the lysosome under amino-acid-replete conditions.

  107. 107.

    Dibble, C. C. & Manning, B. D. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol. 15, 555–564 (2013).

  108. 108.

    Dibble, C. C. et al. TBC1D7 is a third subunit of the TSC1–TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546 (2012).

  109. 109.

    Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).

  110. 110.

    Valvezan, A. J. & Manning, B. D. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333 (2019).

  111. 111.

    Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).

  112. 112.

    Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10, 151–162 (2002).

  113. 113.

    Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014).

  114. 114.

    Demetriades, C., Doumpas, N. & Teleman, A. A. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156, 786–799 (2014). Together with Menon et al. (2014), this study shows that insulin-mediated activation of Akt releases TSC from the lysosome, thereby freeing lysosomal Rheb to activate mTORC1.

  115. 115.

    Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004).

  116. 116.

    Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656 (2004).

  117. 117.

    Inoki, K. et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126, 955–968 (2006).

  118. 118.

    Lee, D. F. et al. IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440–455 (2007).

  119. 119.

    Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

  120. 120.

    Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489–13494 (2004).

  121. 121.

    Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

  122. 122.

    Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).

  123. 123.

    Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

  124. 124.

    Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).

  125. 125.

    Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

  126. 126.

    DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L. W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling. Genes Dev. 22, 239–251 (2008).

  127. 127.

    Demetriades, C., Plescher, M. & Teleman, A. A. Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat. Commun. 7, 10662 (2016).

  128. 128.

    Saveljeva, S. et al. Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival. Oncotarget 7, 12254–12266 (2016).

  129. 129.

    Feng, Z. et al. The regulation of AMPKβ1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1–AKT–mTOR pathways. Cancer Res. 67, 3043–3053 (2007).

  130. 130.

    Blommaart, E. F., Luiken, J. J., Blommaart, P. J., van Woerkom, G. M. & Meijer, A. J. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J. Biol. Chem. 270, 2320–2326 (1995).

  131. 131.

    Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

  132. 132.

    Sancak, Y. et al. Ragulator–Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).

  133. 133.

    Bar-Peled, L., Schweitzer, L. D., Zoncu, R. & Sabatini, D. M. Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208 (2012).

  134. 134.

    Su, M. Y. et al. Hybrid structure of the RagA/C–Ragulator mTORC1 activation complex. Mol. Cell 68, 835–846 (2017).

  135. 135.

    Shen, K., Choe, A. & Sabatini, D. M. Intersubunit crosstalk in the Rag GTPase heterodimer enables mTORC1 to respond rapidly to amino acid availability. Mol. Cell 68, 821 (2017).

  136. 136.

    Rogala, K. B. et al. Structural basis for the docking of mTORC1 on the lysosomal surface. Science 366, 468–475 (2019).

  137. 137.

    Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

  138. 138.

    Shen, K., Valenstein, M. L., Gu, X. & Sabatini, D. M. Arg-78 of Nprl2 catalyzes GATOR1-stimulated GTP hydrolysis by the Rag GTPases. J. Biol. Chem. 294, 2970–2975 (2019).

  139. 139.

    Shen, K. et al. Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes. Nature 556, 64–69 (2018).

  140. 140.

    Peng, M., Yin, N. & Li, M. O. SZT2 dictates GATOR control of mTORC1 signalling. Nature 543, 433–437 (2017).

  141. 141.

    Wolfson, R. L. et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438–442 (2017).

  142. 142.

    Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

  143. 143.

    Saxton, R. A. et al. Structural basis for leucine sensing by the Sestrin2–mTORC1 pathway. Science 351, 53–58 (2016).

  144. 144.

    Ye, J. et al. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 29, 2331–2336 (2015).

  145. 145.

    Chantranupong, L. et al. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8 (2014).

  146. 146.

    Parmigiani, A. et al. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9, 1281–1291 (2014).

  147. 147.

    Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

  148. 148.

    Saxton, R. A., Chantranupong, L., Knockenhauer, K. E., Schwartz, T. U. & Sabatini, D. M. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536, 229–233 (2016).

  149. 149.

    Rebsamen, M. et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519, 477–481 (2015).

  150. 150.

    Wang, S. et al. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188–194 (2015).

  151. 151.

    Lei, H. T., Ma, J., Sanchez Martinez, S. & Gonen, T. Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state. Nat. Struct. Mol. Biol. 25, 522–527 (2018).

  152. 152.

    Shen, K. & Sabatini, D. M. Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proc. Natl Acad. Sci. USA 115, 9545–9550 (2018).

  153. 153.

    Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

  154. 154.

    Petit, C. S., Roczniak-Ferguson, A. & Ferguson, S. M. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J. Cell Biol. 202, 1107–1122 (2013).

  155. 155.

    Tsun, Z. Y. et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52, 495–505 (2013).

  156. 156.

    Wada, S. et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. 30, 2551–2564 (2016).

  157. 157.

    Villegas, F. et al. Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3. Cell Stem Cell 24, 257–270.e8 (2019).

  158. 158.

    Perera, R. M. et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

  159. 159.

    Di Malta, C. et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science 356, 1188–1192 (2017).

  160. 160.

    Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017). Collectively with Wolfson et al. (2016), Saxton et al. (Science, 2016), Chantranupong et al. (2016) and Saxton et al. (Nature, 2016), this study describes the molecular action of the cytoplasmic ‘nutrient sensors’, which bind leucine, arginine and SAM and communicate their availability to the GATOR complexes.

  161. 161.

    Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013).

  162. 162.

    Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11, 390–401 (2010).

  163. 163.

    Hoxhaj, G. et al. The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Rep. 21, 1331–1346 (2017).

  164. 164.

    Emmanuel, N. et al. Purine nucleotide availability regulates mTORC1 activity through the Rheb GTPase. Cell Rep. 19, 2665–2680 (2017). Together with Hoxhaj et al. (2017), this study argues that purine nucleotide availability regulates mTORC1 activity, either by activation of TSC upon acute deprivation and degradation of Rheb under prolonged deprivation (Hoxhaj et al.) or through disruption of Rheb farnesylation (Emmanuel et al.).

  165. 165.

    Menon, D. et al. Lipid sensing by mTOR via de novo synthesis of phosphatidic acid. J. Biol. Chem. 292, 6303–6311 (2017).

  166. 166.

    Jewell, J. L. et al. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194 (2015).

  167. 167.

    Gan, X., Wang, J., Su, B. & Wu, D. Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 286, 10998–11002 (2011).

  168. 168.

    Khanna, A. et al. The small GTPases Ras and Rap1 bind to and control TORC2 activity. Sci. Rep. 6, 25823 (2016).

  169. 169.

    Saci, A., Cantley, Lewis, C. & Carpenter, Christopher L. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol. Cell 42, 50–61 (2011).

  170. 170.

    Senoo, H. et al. Phosphorylated Rho–GDP directly activates mTORC2 kinase towards AKT through dimerization with Ras–GTP to regulate cell migration. Nat. Cell Biol. 21, 867–878 (2019).

  171. 171.

    Kovalski, J. R. et al. The functional proximal proteome of oncogenic Ras includes mTORC2. Mol. Cell 73, 830–844 (2019). Together with Khanna et al. (2016), Saci et al. (2011), and Senoo et al. (2019), this study implicates small GTPases in upstream regulation of mTORC2 activity.

  172. 172.

    Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).

  173. 173.

    Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011).

  174. 174.

    Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).

  175. 175.

    Kazyken, D. et al. AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci. Signal. 12, eaav3249 (2019).

  176. 176.

    Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).

  177. 177.

    Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).

  178. 178.

    Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425 (2005).

  179. 179.

    Peng, M., Yin, N. & Li, M. O. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159, 122–133 (2014).

  180. 180.

    Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

  181. 181.

    Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).

  182. 182.

    Arif, A. et al. EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice. Nature 542, 357–361 (2017).

  183. 183.

    Lee, P. L., Tang, Y., Li, H. & Guertin, D. A. Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease. Mol. Metab. 5, 422–432 (2016).

  184. 184.

    Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008).

  185. 185.

    Hagiwara, A. et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 15, 725–738 (2012).

  186. 186.

    Yuan, M., Pino, E., Wu, L., Kacergis, M. & Soukas, A. A. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem. 287, 29579–29588 (2012).

  187. 187.

    Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003).

  188. 188.

    Howell, J. J. et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 25, 463–471 (2017).

  189. 189.

    Lipton, J. O. & Sahin, M. The neurology of mTOR. Neuron 84, 275–291 (2014).

  190. 190.

    Graber, T. E., McCamphill, P. K. & Sossin, W. S. A recollection of mTOR signaling in learning and memory. Learn Mem. 20, 518–530 (2013).

  191. 191.

    Cloetta, D. et al. Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis. J. Neurosci. 33, 7799–7810 (2013).

  192. 192.

    Thomanetz, V. et al. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 201, 293–308 (2013).

  193. 193.

    Crino, P. B. mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb. Perspect. Med. 5, a022442 (2015).

  194. 194.

    Pilarski, R. et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J. Natl Cancer Inst. 105, 1607–1616 (2013).

  195. 195.

    Puffenberger, E. G. et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain 130, 1929–1941 (2007).

  196. 196.

    Dibbens, L. M. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet. 45, 546 (2013).

  197. 197.

    Weckhuysen, S. et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 57, 994–1003 (2016).

  198. 198.

    Yuskaitis, C. J. et al. A mouse model of DEPDC5-related epilepsy: neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. Neurobiol. Dis. 111, 91–101 (2018).

  199. 199.

    Basel-Vanagaite, L. et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am. J. Hum. Genet. 93, 524–529 (2013).

  200. 200.

    Nakamura, Y. et al. Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease. PLOS ONE 14, e0221482 (2019).

  201. 201.

    Reijnders, M. R. F. et al. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nat. Commun. 8, 1052 (2017).

  202. 202.

    Allen, A. S. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

  203. 203.

    D’Gama, A. M. et al. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep. 21, 3754–3766 (2017).

  204. 204.

    Gallent, E. A. & Steward, O. Neuronal PTEN deletion in adult cortical neurons triggers progressive growth of cell bodies, dendrites, and axons. Exp. Neurol. 303, 12–28 (2018).

  205. 205.

    Abs, E. et al. TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice. Ann. Neurol. 74, 569–579 (2013).

  206. 206.

    McDaniel, S. S., Rensing, N. R., Thio, L. L., Yamada, K. A. & Wong, M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 52, e7–e11 (2011).

  207. 207.

    US National Library of Medicine. (2017).

  208. 208.

    Brandt, C. et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood–brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology 140, 107–120 (2018).

  209. 209.

    Hsu, W.-L. et al. Glutamate stimulates local protein synthesis in the axons of rat cortical neurons by activating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and metabotropic glutamate receptors. J. Biol. Chem. 290, 20748–20760 (2015).

  210. 210.

    Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963 (2008).

  211. 211.

    Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011).

  212. 212.

    Takei, N. et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 24, 9760–9769 (2004).

  213. 213.

    Henry, F. E., Hockeimer, W., Chen, A., Mysore, S. P. & Sutton, M. A. Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation. Mol. Brain 10, 50–50 (2017).

  214. 214.

    Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012).

  215. 215.

    Gkogkas, C. G. et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493, 371–377 (2013).

  216. 216.

    Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959 (2010). This study shows that the behavioural effects of ketamine on murine depression models are mediated by rapid activation of mTOR and an ensuing increase in synaptic translation, synaptic protein levels and synapse number.

  217. 217.

    Kato, T. et al. Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation. J. Clin. Invest. 129, 2542–2554 (2019).

  218. 218.

    Nikoletopoulou, V., Sidiropoulou, K., Kallergi, E., Dalezios, Y. & Tavernarakis, N. Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab. 26, 230–242 (2017).

  219. 219.

    Tang, G. et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131–1143 (2014).

  220. 220.

    Menon, S. & Manning, B. D. Common corruption of the mTOR signaling network in human tumors. Oncogene 27, S43–S51 (2008).

  221. 221.

    Okosun, J. et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat. Genet. 48, 183–188 (2016).

  222. 222.

    Nickerson, M. L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dube syndrome. Cancer Cell 2, 157–164 (2002).

  223. 223.

    Wagle, N. et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4, 546–553 (2014).

  224. 224.

    Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26, 1603–1610 (2008).

  225. 225.

    Palm, W. et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015).

  226. 226.

    Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLOS Biol. 7, e1000038 (2009).

  227. 227.

    Garcia-Martinez, J. M. et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem. J. 421, 29–42 (2009).

  228. 228.

    Ghobrial, I. M. et al. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström’s macroglobulinemia. Am. J. Hematol. 91, 400–405 (2016).

  229. 229.

    Rodrik-Outmezguine, V. S. et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1, 248–259 (2011).

  230. 230.

    Rodrik-Outmezguine, V. S. et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 534, 272–276 (2016).

  231. 231.

    Fan, Q. et al. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell 31, 424–435 (2017). This study finds that a ‘third-generation’ mTOR inhibitor that links a rapalog with an ATP-competitive catalytic inhibitor (described in Rodrik-Outmezguine et al. (2016)) is more effective than either first-generation or second-generation mTOR inhibitors in driving regression of treatment-resistant glioblastomas. The ‘third-generation’ inhibitor combats resistance caused by activating mutations in either the kinase domain or the FKBP12–rapamycin binding domain of mTOR.

  232. 232.

    Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).

  233. 233.

    Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).

  234. 234.

    Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).

  235. 235.

    Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).

  236. 236.

    Wu, J. J. et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 4, 913–920 (2013).

  237. 237.

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This study presents the first report of a pharmacological intervention — rapamycin treatment — capable of extending the maximal lifespan in mammals of both sexes.

  238. 238.

    Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006).

  239. 239.

    Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).

  240. 240.

    Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).

  241. 241.

    Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016).

  242. 242.

    Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).

  243. 243.

    Grandison, R. C., Piper, M. D. W. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061–1064 (2009).

  244. 244.

    Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

  245. 245.

    Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018).

  246. 246.

    Fernandez, A. F. et al. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558, 136–140 (2018).

  247. 247.

    Toth, M. L. et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330–338 (2008).

  248. 248.

    Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLOS Genet. 4, e24 (2008).

  249. 249.

    Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).

  250. 250.

    Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).

  251. 251.

    Carroll, B. et al. Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. J. Cell Biol. 216, 1949 (2017). This study shows that mTORC1 activation is constitutive and insensitive to deprivation of growth factors or nutrients in senescent human fibroblasts, perhaps due to defects in membrane potential. Strikingly, this study also found that starvation coupled to mTOR inhibition selectively promotes senescent cell death.

  252. 252.

    Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015).

  253. 253.

    Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).

  254. 254.

    Arriola Apelo, S. I. et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15, 28–38 (2016).

  255. 255.

    Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent administration of rapamycin extends the life span of female C57BL/6J mice. J. Gerontol. A Biol. Sci. Med. Sci. 71, 876–881 (2016).

  256. 256.

    Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018).

  257. 257.

    Lim, C.-Y. et al. ER–lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann–Pick type C. Nat. Cell Biol. 21, 1206–1218 (2019).

  258. 258.

    Hao, F. et al. Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi–lysosome contact site. J. Cell Sci. 131, jcs208017 (2018).

  259. 259.

    Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460 (2011).

  260. 260.

    Manifava, M. et al. Dynamics of mTORC1 activation in response to amino acids. eLife 5, e19960 (2016).

  261. 261.

    Ahmed, A. R. et al. Direct imaging of the recruitment and phosphorylation of S6K1 in the mTORC1 pathway in living cells. Sci. Rep. 9, 3408 (2019).

  262. 262.

    Naito, T., Kuma, A. & Mizushima, N. Differential contribution of insulin and amino acids to the mTORC1–autophagy pathway in the liver and muscle. J. Biol. Chem. 288, 21074–21081 (2013).

  263. 263.

    Frey, J. W., Jacobs, B. L., Goodman, C. A. & Hornberger, T. A. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell Signal. 26, 313–322 (2014).

  264. 264.

    You, J. S. et al. The role of raptor in the mechanical load-induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy. FASEB J. 33, 4021–4034 (2019).

  265. 265.

    Jacobs, B. L. et al. Eccentric contractions increase the phosphorylation of tuberous sclerosis complex-2 (TSC2) and alter the targeting of TSC2 and the mechanistic target of rapamycin to the lysosome. J. Physiol. 591, 4611–4620 (2013).

  266. 266.

    Wang, A. et al. Activity-independent targeting of mTOR to lysosomes in primary osteoclasts. Sci. Rep. 7, 3005 (2017).

  267. 267.

    Stracka, D., Jozefczuk, S., Rudroff, F., Sauer, U. & Hall, M. N. Nitrogen source activates TOR (target of rapamycin) complex 1 via glutamine and independently of Gtr/Rag proteins. J. Biol. Chem. 289, 25010–25020 (2014). This study finds that nitrogen sources can activate TORC1 in prototrophic yeast strains in a transient, Rag-dependent manner, although sustained activation by glutamine may feed through an alternative mechanism.

  268. 268.

    Urano, J., Tabancay, A. P., Yang, W. & Tamanoi, F. The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake. J. Biol. Chem. 275, 11198–11206 (2000).

  269. 269.

    Otsubo, Y. & Yamamato, M. TOR signaling in fission yeast. Crit. Rev. Biochem. Mol. Biol. 43, 277–283 (2008).

  270. 270.

    Wolfson, R. L. & Sabatini, D. M. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 26, 301–309 (2017).

  271. 271.

    Piyankarage, S. C., Augustin, H., Grosjean, Y., Featherstone, D. E. & Shippy, S. A. Hemolymph amino acid analysis of individual Drosophila larvae. Anal. Chem. 80, 1201–1207 (2008).

  272. 272.

    Algret, R. et al. Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway. Mol. Cell Proteom. 13, 2855 (2014).

  273. 273.

    Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983 (2013).

  274. 274.

    Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005).

  275. 275.

    Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R. & Lee, V. M. Y. Lewy body-like α-Synuclein aggregates resist degradation and impair macroautophagy. J. Biol. Chem. 288, 15194–15210 (2013).

  276. 276.

    Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

  277. 277.

    Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

  278. 278.

    Kaeberlein, M. & Galvan, V. Rapamycin and Alzheimer’s disease: time for a clinical trial? Sci. Transl. Med. 11, eaar4289 (2019).

  279. 279.

    Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson’s disease. J. Neurosci. 30, 12535 (2010).

  280. 280.

    Santini, E., Heiman, M., Greengard, P., Valjent, E. & Fisone, G. Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2, ra36 (2009).

  281. 281.

    Castellano, B.M. et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann–Pick C1 signaling complex. Science 355, 1306–1311 (2017).

Download references


The authors thank all members of the Sabatini laboratory for helpful discussions, with particular gratitude to K. J. Condon and J. M. Orozco for their insightful comments on this manuscript and K. Shen for his assistance with Fig. 1. This work was supported by grants from the National Institutes of Health (NIH) (R01 CA103866, R01 CA129105 and R37 AI047389) and the Lustgarten Foundation to D.M.S and by fellowship funding from the NIH (T32 GM007287 and F31 CA232340) to G.Y.L. D.M.S. is an Investigator at the Howard Hughes Medical Institute and an American Cancer Society Research Professor.

Author information

G.Y.L. researched the data, discussed content and wrote the first full draft of the manuscript. D.M.S discussed article content and was involved in editing and revising the manuscript.

Correspondence to David M. Sabatini.

Ethics declarations

Competing interests

D.M.S. is a founder and a member of the scientific advisory board for Navitor Pharmaceuticals, which targets the mTORC1 pathway for therapeutic benefit.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.



A double-membraned vesicle that forms during the early stages of autophagy to engulf cellular cargo (organelles and macromolecules). The autophagosome fuses with the lysosome to degrade macromolecules into constituent amino acids or fatty acids, enabling their reuse elsewhere in the cell.


A non-selective endocytic process in which cells take up soluble nutrients and macromolecules from the extracellular medium. These molecules are eventually degraded and recycled in the lysosome.

Endoplasmic reticulum unfolded protein response

A stress pathway activated by unfolded proteins in the endoplasmic reticulum lumen that upregulates chaperones, selectively degrades the mRNA of secretory proteins and reduces global protein synthesis.

GTP exchange factor

A factor that catalyses the loading of GTP in place of GDP to activate a given small G protein.


A condition in which the head is abnormally small owing to a brain that fails to grow and fully develop. Microcephaly is often coupled to developmental abnormalities and cognitive deficits.

Brain-derived neurotrophic factor

(BDNF). A member of the neurotrophin growth factor family that binds to tropomyosin receptor kinase B (Trkb) to stimulate the growth and differentiation of new neurons and synapses. BDNF may regulate synaptic plasticity, learning and memory.

Dendritic spines

Small protrusions on dendrites that receive excitatory synaptic inputs and undergo morphological alterations to modulate synaptic strength. Because these spines are structured by the actin cytoskeleton, they are sensitive to mTOR complex 2 activity, such that mice lacking Rictor in the brain fail to convert early long-term potentiation into long-term memory.

Long-term potentiation

A process in which synapses in neurons become selectively stronger in response to frequent activation. Long-term potentiation and long-term depression (the weakening of a synapse after persistent or patterned activation) may underlie neuronal plasticity by allowing the brain to change after an experience.

NMDA receptor

An ionotropic glutamate receptor found at many excitatory synapses. Upon binding to the neurotransmitter glutamate, this receptor opens a cation channel, allowing calcium ions to flow into the neuron. Ketamine binds the NMDA receptor and antagonizes its activation by glutamate.

Synaptic pruning

A regulated process in which axons and dendrites are eliminated to remove unnecessary synapses in an experience-dependent fashion. In humans, pruning occurs primarily during childhood and after adolescence.

Senescent cells

Cells that have arrested in a quasi-G0 state and no longer divide. Often induced by insults associated with cellular ageing, the senescent state is also accompanied by morphological and metabolic changes that induce chromosomal remodelling, constitutive autophagy and secretion of inflammatory factors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, G.Y., Sabatini, D.M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol (2020).

Download citation