Review Article | Published:

mTOR as a central hub of nutrient signalling and cell growth

Nature Cell Biologyvolume 21pages6371 (2019) | Download Citation

Abstract

The highly conserved protein kinase mechanistic target of rapamycin (mTOR; originally known as mammalian target of rapamycin) is a central cell growth regulator connecting cellular metabolism and growth with a wide range of environmental inputs as part of mTOR complex 1 (mTORC1) and mTORC2. In this Review, we introduce the landmark discoveries in the mTOR field, starting from the isolation of rapamycin to the molecular characterizations of key components of the mTORC signalling network with an emphasis on amino acid sensing, and discuss the perspectives of mTORC inhibitors in therapeutic applications.

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References

  1. 1.

    Sabatini, D. M. Twenty-five years of mTOR: uncovering the link from nutrients to growth. Proc. Natl Acad. Sci. USA 114, 11818–11825 (2017).

  2. 2.

    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).

  3. 3.

    Baker, H., Sidorowicz, A., Sehgal, S. N. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. J. Antibiot. 31, 539–545 (1978).

  4. 4.

    Douros, J. & Suffness, M. New antitumor substances of natural origin. Cancer Treat. Rev. 8, 63–87 (1981).

  5. 5.

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

  6. 6.

    Sehgal, S. N. & Bansbach, C. C. Rapamycin: in vitro profile of a new immunosuppressive macrolide. Ann. NY Acad. Sci. 685, 58–67 (1993).

  7. 7.

    Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. & Sigal, N. H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J. Immunol. 144, 251–258 (1990).

  8. 8.

    Dumont, F. J. et al. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J. Immunol. 144, 1418–1424 (1990).

  9. 9.

    Schreiber, S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 251, 283–287 (1991).

  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.

    Heitman, J., Movva, N. R., Hiestand, P. C. & Hall, M. N. FK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 88, 1948–1952 (1991).

  12. 12.

    Koltin, Y. et al. Rapamycin sensitivity in Saccharomyces cerevisiae is mediated by a peptidyl-prolyl cistrans isomerase related to human FK506-binding protein. Mol. Cell. Biol. 11, 1718–1723 (1991).

  13. 13.

    Wiederrecht, G., Brizuela, L., Elliston, K., Sigal, N. H. & Siekierka, J. J. FKB1 encodes a nonessential FK 506-binding protein in Saccharomyces cerevisiae and contains regions suggesting homology to the cyclophilins. Proc. Natl Acad. Sci. USA 88, 1029–1033 (1991).

  14. 14.

    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).

  15. 15.

    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).

  16. 16.

    Stan, R. et al. Interaction between FKBP12–rapamycin and TOR involves a conserved serine residue. J. Biol. Chem. 269, 32027–32030 (1994).

  17. 17.

    Zheng, X. F., Florentino, D., Chen, J., Crabtree, G. R. & Schreiber, S. L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121–130 (1995).

  18. 18.

    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).

  19. 19.

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

  20. 20.

    Chiu, M. I., Katz, H. & Berlin, V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl Acad. Sci. USA 91, 12574–12578 (1994).

  21. 21.

    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).

  22. 22.

    Singh, K., Sun, S. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action. J. Antibiot. 32, 630–645 (1979).

  23. 23.

    Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15, 658–664 (1996).

  24. 24.

    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).

  25. 25.

    Kuo, C. J. et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358, 70–73 (1992).

  26. 26.

    Barbet, N. C. et al. TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell 7, 25–42 (1996).

  27. 27.

    Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000).

  28. 28.

    Hentges, K. E. et al. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc. Natl Acad. Sci. USA 98, 13796–13801 (2001).

  29. 29.

    Xiong, Y. & Sheen, J. Novel links in the plant TOR kinase signaling network. Curr. Opin. Plant Biol. 28, 83–91 (2015).

  30. 30.

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

  31. 31.

    Schmidt, A., Kunz, J. & Hall, M. N. TOR2 is required for organization of the actin cytoskeleton in yeast. Proc. Natl Acad. Sci. USA 93, 13780–13785 (1996).

  32. 32.

    Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).

  33. 33.

    Reinke, A. et al. TOR complex 1 includes a novel component, Tco89p (YPL180w), and cooperates with Ssd1p to maintain cellular integrity in Saccharomyces cerevisiae. J. Biol. Chem. 279, 14752–14762 (2004).

  34. 34.

    Adami, A., Garcia-Alvarez, B., Arias-Palomo, E., Barford, D. & Llorca, O. Structure of TOR and its complex with KOG1. Mol. Cell 27, 509–516 (2007).

  35. 35.

    Wullschleger, S., Loewith, R., Oppliger, W. & Hall, M. N. Molecular organization of target of rapamycin complex 2. J. Biol. Chem. 280, 30697–30704 (2005).

  36. 36.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 169, 361–371 (2017).

  37. 37.

    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).

  38. 38.

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

  39. 39.

    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).

  40. 40.

    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).

  41. 41.

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

  42. 42.

    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).

  43. 43.

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

  44. 44.

    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).

  45. 45.

    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).

  46. 46.

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

  47. 47.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

  48. 48.

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

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 52.

    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).

  53. 53.

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

  54. 54.

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

  55. 55.

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

  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.

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

  60. 60.

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

  61. 61.

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

  62. 62.

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

  63. 63.

    Lee, G. et al. Post-transcriptional regulation of de novo lipogenesis by mTORC1–S6K1–SRPK2 signaling. Cell 171, 1545–1558 (2017).

  64. 64.

    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).

  65. 65.

    Garcia-Martinez, J. M. & Alessi, D. R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416, 375–385 (2008).

  66. 66.

    Kim, S. J. et al. mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol. Cell 48, 875–887 (2012).

  67. 67.

    Sengupta, S. et al. Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proc. Natl Acad. Sci. USA 110, 18826–18831 (2013).

  68. 68.

    Sciarretta, S. et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep. 11, 125–136 (2015).

  69. 69.

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

  70. 70.

    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).

  71. 71.

    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).

  72. 72.

    Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345–1356 (2006).

  73. 73.

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

  74. 74.

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

  75. 75.

    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).

  76. 76.

    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).

  77. 77.

    Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658–665 (2002).

  78. 78.

    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).

  79. 79.

    Carroll, B. et al. Control of TSC2–Rheb signaling axis by arginine regulates mTORC1 activity. eLife 5, e11058 (2016).

  80. 80.

    Guertin, D. A. & Sabatini, D. M. An expanding role for mTOR in cancer. Trends Mol. Med 11, 353–361 (2005).

  81. 81.

    Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

  82. 82.

    Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. 10, 594–601 (2004).

  83. 83.

    Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten± mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).

  84. 84.

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

  85. 85.

    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).

  86. 86.

    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).

  87. 87.

    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).

  88. 88.

    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).

  89. 89.

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

  90. 90.

    Roccio, M., Bos, J. L. & Zwartkruis, F. J. Regulation of the small GTPase Rheb by amino acids. Oncogene 25, 657–664 (2006).

  91. 91.

    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).

  92. 92.

    Dubouloz, F., Deloche, O., Wanke, V., Cameroni, E. & De Virgilio, C. The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol. Cell 19, 15–26 (2005).

  93. 93.

    Gao, M. & Kaiser, C. A. A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat. Cell Biol. 8, 657–667 (2006).

  94. 94.

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

  95. 95.

    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).

  96. 96.

    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).

  97. 97.

    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).

  98. 98.

    Jewell, J. L. et al. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194–198 (2015).

  99. 99.

    Li, L. et al. Regulation of mTORC1 by the Rab and Arf GTPases. J. Biol. Chem. 285, 19705–19709 (2010).

  100. 100.

    Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

  101. 101.

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

  102. 102.

    Tan, H. W. S., Sim, A. Y. L. & Long, Y. C. Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation. Nat. Commun. 8, 338 (2017).

  103. 103.

    Csibi, A. et al. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr. Biol. 24, 2274–2280 (2014).

  104. 104.

    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).

  105. 105.

    Kim, J. & Guan, K. L. Amino acid signaling in TOR activation. Annu. Rev. Biochem. 80, 1001–1032 (2011).

  106. 106.

    Binda, M. et al. The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35, 563–573 (2009).

  107. 107.

    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).

  108. 108.

    Deng, L. et al. The ubiquitination of Rag A GTPase by RNF152 negatively regulates mTORC1 activation. Mol. Cell 58, 804–818 (2015).

  109. 109.

    Jin, G. et al. Skp2-mediated RagA ubiquitination elicits a negative feedback to prevent amino-acid-dependent mTORC1 hyperactivation by recruiting GATOR1. Mol. Cell 58, 989–1000 (2015).

  110. 110.

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

  111. 111.

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

  112. 112.

    Kim, Y. M. et al. SH3BP4 is a negative regulator of amino acid–Rag GTPase–mTORC1 signaling. Mol. Cell 46, 833–846 (2012).

  113. 113.

    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).

  114. 114.

    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).

  115. 115.

    Baba, M. et al. Kidney-targeted Birt–Hogg–Dube gene inactivation in a mouse model: Erk1/2 and Akt–mTOR activation, cell hyperproliferation, and polycystic kidneys. J. Natl Cancer Inst. 100, 140–154 (2008).

  116. 116.

    Han, J. M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012).

  117. 117.

    Bonfils, G. et al. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell 46, 105–110 (2012).

  118. 118.

    He, X. D. et al. Sensing and transmitting intracellular amino acid signals through reversible lysine aminoacylations. Cell Metab. 27, 151–166 (2018).

  119. 119.

    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).

  120. 120.

    Jung, J., Genau, H. M. & Behrends, C. Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol. Cell. Biol. 35, 2479–2494 (2015).

  121. 121.

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

  122. 122.

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

  123. 123.

    Budanov, A. V. et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21, 6017–6031 (2002).

  124. 124.

    Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).

  125. 125.

    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).

  126. 126.

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

  127. 127.

    Saxton, R. A. et al. Structural basis for leucine sensing by the sestrin2–mTORC1 pathway. Science 351, 53–58 (2016).

  128. 128.

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

  129. 129.

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

  130. 130.

    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).

  131. 131.

    Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

  132. 132.

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

  133. 133.

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

  134. 134.

    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).

  135. 135.

    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).

  136. 136.

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

  137. 137.

    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).

  138. 138.

    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).

  139. 139.

    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).

  140. 140.

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

  141. 141.

    Munson, M. J. et al. mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO J. 34, 2272–2290 (2015).

  142. 142.

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

  143. 143.

    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).

  144. 144.

    Grabiner, B. C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563 (2014).

  145. 145.

    Kim, L. C., Cook, R. S. & Chen, J. mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36, 2191–2201 (2017).

  146. 146.

    Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP–eIF4E. Cancer Cell 17, 249–261 (2010).

  147. 147.

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

  148. 148.

    Alain, T. et al. eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res. 72, 6468–6476 (2012).

  149. 149.

    She, Q. B. et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18, 39–51 (2010).

  150. 150.

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

  151. 151.

    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).

  152. 152.

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

  153. 153.

    Johnson, C. E. & Tee, A. R. Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. Essays Biochem. 61, 699–710 (2017).

  154. 154.

    Rangwala, R. et al. Combined mTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391–1402 (2014).

  155. 155.

    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).

  156. 156.

    Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).

  157. 157.

    Schenone, S., Brullo, C., Musumeci, F., Radi, M. & Botta, M. ATP-competitive inhibitors of mTOR: an update. Curr. Med. Chem. 18, 2995–3014 (2011).

  158. 158.

    Zou, Z. Q. et al. A novel dual PI3Kα/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. Int. J. Mol. Med. 24, 97–101 (2009).

  159. 159.

    Wagle, N. et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371, 1426–1433 (2014).

  160. 160.

    Fan, Q. et al. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell 31, 424–435 (2017).

  161. 161.

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

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Acknowledgements

This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Education in Korea (no. 2015R1D1A1A01059401 and no. 2018R1D1A1B07048869 to J.K.) and by grants from the National Institutes of Health (GM51586, CA196878 and CA217642 to K.-L.G.). K.-L.G. is a co-founder and has an equity interest in Vivace Therapeutics, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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  1. Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul, Korea

    • Joungmok Kim
  2. Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    • Kun-Liang Guan

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The authors declare no competing interests.

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Correspondence to Joungmok Kim or Kun-Liang Guan.

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https://doi.org/10.1038/s41556-018-0205-1

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