Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Making new contacts: the mTOR network in metabolism and signalling crosstalk

Nature Reviews Molecular Cell Biology volume 15, pages 155–162 (2014)Cite this article

Subjects

Abstract

More than 20 years after its discovery, our understanding of target of rapamycin (TOR) signalling continues to grow. Recent global 'omics' studies have revealed physiological roles of mammalian TOR (mTOR) in protein, nucleotide and lipid synthesis. Furthermore, emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling. Together, this progress has expanded the list of downstream effectors and upstream regulators of mTOR signalling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Upstream of mTOR: classical and non-classical inputs.
Figure 2: mTOR controls metabolism.

Similar content being viewed by others

References

  1. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nature Rev. Mol. Cell Biol. 10, 307–318 (2009).

    Article  CAS  Google Scholar 

  7. Mamane, Y. Petroulakis, E., LeBacquer, O. & Sonenberg, N. mTOR, translation initiation and cancer. Oncogene 25, 6416–6422 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Jewell, J. L., Russell, R. C. & Guan, K. L. Amino acid signalling upstream of mTOR. Nature Rev. Mol. Cell Biol. 14, 133–139 (2013).

    Article  CAS  Google Scholar 

  9. Mieulet, V. & Lamb, R. F. Tuberous sclerosis complex: linking cancer to metabolism. Trends Mol. Med. 16, 329–335 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Cybulski, N. & Hall, M. N. TOR complex 2: a signaling pathway of its own. Trends Biochem. Sci. 34, 620–627 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Sparks, C. A. & Guertin, D. A. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29, 3733–3744 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl Acad. Sci. USA 109, 8977–8982 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chauvin, C. et al. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474–483 (2013).

    Article  PubMed  CAS  Google Scholar 

  22. Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, X. et al. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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, C712–722 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dowling, R. J. et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328, 1172–1176 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oh, W. J. et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J. 29, 3939–3951 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dai, N., Christiansen, J. & Nielsen, F. C. & Avruch, J. mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts. Genes Dev. 27, 301–312 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Csibi, A. et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153, 840–854 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Kenerson, H. L., Yeh, M. M. & Yeung, R. S. Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation. PLoS ONE 6, e18075 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yecies, J. L. et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell. Metab. 14, 21–32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cornu, M., Albert, V. & Hall, M. N. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Lamming, D. W. & Sabatini, D. M. A central role for mTOR in lipid homeostasis. Cell. Metab. 18, 465–469 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ricoult, S. J. & Manning, B. D. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 14, 242–251 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jung, C. H. et al. ULK–Atg13–FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature Cell Biol. 15, 741–750 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Yuan, H. X., Russell, R. C. & Guan, K. L. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9, 1983–1995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Koren, I., Reem, E. & Kimchi, A. DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr. Biol. 20, 1093–1098 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Martina, J. A. & Puertollano, R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 200, 475–491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pena-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kim, S. G. et al. Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT–RUVBL1/2 complex. Mol. Cell 49, 172–185 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature Cell Biol. 13, 877–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Tumaneng, K. et al. YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29. Nature Cell Biol. 14, 1322–1329 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Miller, E. et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem. Biol. 19, 955–962 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).

    Article  CAS  Google Scholar 

  63. Niehrs, C. The complex world of WNT receptor signalling. Nature Rev. Mol. Cell Biol. 13, 767–779 (2012).

    Article  CAS  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. Valvezan, A. J., Huang, J., Lengner, C. J., Pack, M. & Klein, P. S. Oncogenic mutations in adenomatous polyposis coli (Apc) activate mechanistic target of rapamycin complex 1 (mTORC1) in mice and zebrafish. Dis. Model. Mech. 7, 63–71 (2014).

    CAS  PubMed  Google Scholar 

  66. Esen, E. et al. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell. Metab. 17, 745–755 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bray, S. J. Notch signalling: a simple pathway becomes complex. Nature Rev. Mol. Cell Biol. 7, 678–689 (2006).

    Article  CAS  Google Scholar 

  68. Pajvani, U. B. et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nature Med. 19, 1054–1060 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Morita, M. et al. mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation. Cell. Metab. 18, 698–711 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Betz, C. & Hall, M. N. Where is mTOR and what is it doing there? J. Cell Biol. 203, 563–574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chaveroux, C. et al. Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell. Metab. 17, 586–598 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol. 10, 935–945 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Duran, R. V. et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol. Cell 47, 349–358 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Duran, R. V. et al. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene 32, 4549–4556 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Panchaud, N., Peli-Gulli, M. P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal 6, ra42 (2013).

    Article  PubMed  CAS  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov. 10, 868–880 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the Louis-Jeantet Foundation, the Swiss National Science Foundation and the Canton of Basel.

Author information

Authors and Affiliations

  1. Biozentrum, University of Basel, Basel, 4056, Switzerland

    Mitsugu Shimobayashi & Michael N. Hall

Authors
  1. Mitsugu Shimobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael N. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael N. Hall.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shimobayashi, M., Hall, M. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15, 155–162 (2014). https://doi.org/10.1038/nrm3757

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3757

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing