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Amino acid signalling upstream of mTOR

Abstract

Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H+-ATPase (v-ATPase).

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Figure 1: The mTORC1 signalling pathway.
Figure 2: Amino acid-induced mTORC1 activation in mammals and yeast.
Figure 3: mTORC1 activation at the lysosome.

References

  1. 1

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).

    CAS  Article  Google Scholar 

  3. 3

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Wang, X., Campbell, L. E., Miller, C. M. & Proud, C. G. Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem. J. 334, 261–267 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Bauchart-Thevret, C., Cui, L., Wu, G. & Burrin, D. G. Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. Am. J. Physiol. Endocrinol. Metab. 299, e899–e909 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    van der Vos, K. E. & Coffer, P. J. Glutamine metabolism links growth factor signaling to the regulation of autophagy. Autophagy 8, 1862–1864 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    van der Vos, K. E. et al. Modulation of glutamine metabolism by the PI(3)K–PKB–FOXO network regulates autophagy. Nature Cell Biol. 14, 829–837 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Smith, E. M., Finn, S. G., Tee, A. R., Browne, G. J. & Proud, C. G. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. 280, 18717–18727 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Long, X., Ortiz-Vega, S., Lin, Y. & Avruch, J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J. Biol. Chem. 280, 23433–23436 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Nakashima, N., Noguchi, E. & Nishimoto, T. Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics 152, 853–867 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Sekiguchi, T. et al. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J. Biol. Chem. 276, 7246–7257 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gong, R. et al. Crystal structure of the Gtr1p–Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev. 25, 1668–1673 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Jeong, J. H. et al. Crystal structure of the Gtr1pGTP–Gtr2pGDP protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion. J. Biol. Chem. 287, 29648–29653 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    De Virgilio, C. & Loewith, R. Cell growth control: little eukaryotes make big contributions. Oncogene 25, 6392–6415 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ashrafi, K., Farazi, T. A. & Gordon, J. I. A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N-myristoylation during entry into stationary phase. J. Biol. Chem. 273, 25864–25874 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Kogan, K., Spear, E. D., Kaiser, C. A. & Fass, D. Structural conservation of components in the amino acid sensing branch of the TOR pathway in yeast and mammals. J. Mol. Biol. 402, 388–398 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Loewith, R. & Hall, M. N. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189, 1177–1201 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Zhang, T., Peli-Gulli, M. P., Yang, H., De Virgilio, C. & Ding, J. Ego3 functions as a homodimer to mediate the interaction between Gtr1–Gtr2 and Ego1 in the EGO complex to activate TORC1. Structure 20, 2151–2160 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Garcia-Saez, I., Lacroix, F. B., Blot, D., Gabel, F. & Skoufias, D. A. Structural characterization of HBXIP: the protein that interacts with the anti-apoptotic protein survivin and the oncogenic viral protein HBx. J. Mol. Biol. 405, 331–340 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Kurzbauer, R. et al. Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogen-activated protein kinase signaling to late endosomes. Proc. Natl Acad. Sci. USA 101, 10984–10989 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lunin, V. V. et al. The structure of the MAPK scaffold, MP1, bound to its partner, p14. A complex with a critical role in endosomal map kinase signaling. J. Biol. Chem. 279, 23422–23430 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Valbuena, N., Guan, K. L. & Moreno, S. The Vam6–Gtr1/Gtr2 pathway activates TORC1 in response to amino acids in fission yeast. J. Cell Sci. 125, 1920–1928 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Messler, S. et al. The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology 216, 343–350 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Nishi, T. & Forgac, M. The vacuolar (H+)-ATPases — nature's most versatile proton pumps. Nature Rev. Mol. Cell Biol. 3, 94–103 (2002).

    CAS  Article  Google Scholar 

  36. 36

    Fonseca, B. D. et al. Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem. 287, 17530–17545 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Balgi, A. D. et al. Regulation of mTORC1 signaling by pH. PLoS ONE 6, e21549 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

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

    CAS  Article  PubMed  Google Scholar 

  39. 39

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Avruch, J. et al. Amino acid regulation of TOR complex 1. Am. J. Physiol. Endocrinol. Metab. 296, e592–e602 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Mizushima, N. & Klionsky, D. J. Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40 (2007).

    CAS  Article  Google Scholar 

  44. 44

    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).

    CAS  Article  PubMed  Google Scholar 

  45. 45

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

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

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Orlova, M., Kanter, E., Krakovich, D. & Kuchin, S. Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae. Eukaryot. Cell 5, 1831–1837 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Wang, Z., Wilson, W. A., Fujino, M. A. & Roach, P. J. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol. Cell. Biol. 21, 5742–5752 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Hirose, E., Nakashima, N., Sekiguchi, T. & Nishimoto, T. RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1–GTPase pathway. J. Cell Sci. 111, 11–21 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Nakashima, N., Noguchi, E. & Nishimoto, T. Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics 152, 853–867 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to their colleague R. Gong and the rest of the Guan laboratory for valuable discussions and insightful comments. In addition, the authors would like to thank V. S. Tagliabracci for critical reading of this manuscript. The authors would like to apologize to their colleagues whose work could not be cited owing to space limitations. The work in the Guan laboratory was supported by a National Institutes of Health (NIH) grant (CA108941) and a grant from the Department of Defense (W81XWH-09-1-0279) to K.L.G. J.L.J is supported by a grant from the National Cancer Institute (T32CA121938), and R.C.R is supported by a grant from the Canadian Institute of Health Research (CIHR).

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Correspondence to Kun-Liang Guan.

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Jewell, J., Russell, R. & Guan, KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14, 133–139 (2013). https://doi.org/10.1038/nrm3522

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