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.

  • Review Article
  • Published:

TOR signalling in bugs, brain and brawn

Nature Reviews Molecular Cell Biology volume 4, pages 117–126 (2003)Cite this article

A Correction to this article was published on 01 March 2003

Key Points

  • The target of rapamycin (TOR) signalling pathway is a central controller of cell growth.

  • TOR is a highly conserved kinase. It is a member of the phosphatidylinositol kinase-related protein kinase (PIKK) family. It contains HEAT repeats, a FAT domain, an FRB domain and a catalytic domain.

  • TOR forms a complex with several proteins. In yeast, there are two TOR complexes (TORC1 and TORC2). TORC1 contains TOR1 or TOR2 and the evolutionarily conserved proteins KOG1 and LST8. TORC1 mediates the signalling pathways that control rapamycin-sensitive, growth-related processes in response to nutrients. TORC2 contains TOR2, AVO1, AVO2, AVO3, and LST8. TORC2 mediates the signalling pathway that controls actin cytoskeleton organization. Mammalian TOR (mTOR) forms a complex with raptor (mKOG1) and mLST8, and is known as the nutrient-sensitive complex.

  • TOR controls translation, protein stability and transcription in both yeast and mammals.

  • In yeast, TOR is regulated by nutrients. In mammals, mTOR is regulated by nutrients and growth factors such as insulin. mTOR and the insulin signalling pathways converge on S6K and 4E-BP. Amino acids and growth factors might signal to TOR by inhibiting the TSC complex.

  • TOR regulates protein phosphatases. The regulation of phosphatases by TOR ensures a rapid and coordinated response to nutrient deprivation.

  • Studies of the TOR signalling pathway in Drosophila highlight the role of this pathway in the control of cell and organism size.

  • mTOR also controls the growth of non-proliferating cells, such as neurons and muscles, by the control of translation.

Abstract

TOR — a highly conserved atypical protein kinase and the 'target of rapamycin', an immunosuppressant and anti-cancer drug — controls cell growth. TOR controls the growth of proliferating yeast, fly and mammalian cells in response to nutrients. Recent findings, however, indicate that TOR also controls the growth of non-proliferating cells, such as neurons and muscle cells. Furthermore, TOR, by associating with regulatory proteins and inhibiting phosphatases, controls the activity of multiphosphorylated effectors.

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: Structural domains of TOR and its binding partners.
Figure 2: Two functionally distinct TOR complexes in yeast.
Figure 3: mTOR integrates signals from nutrients and growth factors leading to cell growth.
Figure 4: A TOR-signalling defect in Drosophila causes smaller cells and a smaller animal.

Similar content being viewed by others

References

  1. Waite, K. A. & Eng, C. Protean PTEN: form and function. Am. J. Hum. Genet. 70, 829–844 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Hengstschlager, M. Tuberous sclerosis complex genes: from flies to human genetics. Arch. Dermatol. Res. 293, 383–386 (2001).

    CAS  PubMed  Google Scholar 

  3. Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    CAS  PubMed  Google Scholar 

  4. Conlon, I. & Raff, M. Size control in animal development. Cell 96, 235–244 (1999). An insightful review on the whys and hows of size control. This review discusses how cell size and number determine animal size.

    CAS  PubMed  Google Scholar 

  5. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000). A comprehensive review on how the TOR signalling pathway in both yeast and mammals controls cell growth.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Weisman, R. & Choder, M. The fission yeast TOR homolog, tor1+, is required for the response to starvation and other stresses via a conserved serine. J. Biol. Chem. 276, 7027–7032 (2001).

    CAS  PubMed  Google Scholar 

  10. Cruz, M. C. et al. Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans. Mol. Cell. Biol. 19, 4101–4112 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Menand, B. et al. Expression and disruption of the Arabidopsis TOR (target of rapamycin) gene. Proc. Natl Acad. Sci. USA 99, 6422–6427 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Long, X. et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr. Biol. 12, 1448 (2002).

    CAS  PubMed  Google Scholar 

  13. Oldham, S., Montagne, J., Radimerski, T., Thomas, G. & Hafen, E. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 14, 2689–2694 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. 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).

    CAS  PubMed  Google Scholar 

  17. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Keith, C. T. & Schreiber, S. L. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270, 50–51 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Isotani, S. et al. Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase α in vitro. J. Biol. Chem. 274, 34493–34498 (1999).

    CAS  PubMed  Google Scholar 

  22. Andrade, M. A. & Bork, P. HEAT repeats in the Huntington's disease protein. Nature Genet. 11, 115–116 (1995).

    CAS  PubMed  Google Scholar 

  23. Bosotti, R., Isacchi, A. & Sonnhammer, E. L. FAT: a novel domain in PIK-related kinases. Trends Biochem. Sci. 25, 225–227 (2000).

    CAS  PubMed  Google Scholar 

  24. 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). This paper describes two structurally and functionally distinct TOR complexes in yeast (TORC1 and TORC2), and provides the molecular basis for the signalling specificity of TOR. It shows that TORC1 and possibly TORC2 are conserved.

    CAS  PubMed  Google Scholar 

  25. Roberg, K. J., Bickel, S., Rowley, N. & Kaiser, C. A. Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8. Genetics 147, 1569–1584 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu, Z., Sekito, T., Epstein, C. B. & Butow, R. A. RTG-dependent mitochondria to nucleus signaling is negatively regulated by the seven WD-repeat protein Lst8p. EMBO J. 20, 7209–7219 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. 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). References 27 and 28 provide evidence that raptor is required for mTOR regulation of 4E-BP and S6K. Some discrepancies on the nutrient and rapamycin sensitivity of the mTOR/raptor complex and the role of raptor on mTOR kinase activity might stem from different experimental conditions.

    CAS  PubMed  Google Scholar 

  29. Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling. Nature Cell Biol. 4, 699–704 (2002).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002). References 29–31 and 57 provide complementary evidence on how the TSC complex is negatively regulated by Akt, and how the TSCs negatively regulate TOR.

    CAS  PubMed  Google Scholar 

  32. Barbet, N. C. et al. TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell 7, 25–42 (1996). The first paper to propose TOR as a controller of cell growth, and the first paper to present evidence that TOR responds to nutrients.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cardenas, M. E., Cutler, N. S., Lorenz, M. C., Di Como, C. J. & Heitman, J. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13, 3271–3279 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hardwick, J. S., Kuruvilla, F. G., Tong, J. K., Shamji, A. F. & Schreiber, S. L. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc. Natl Acad. Sci. USA 96, 14866–14870 (1999). References 34, 35 and 45 provide compelling evidence on the negative regulatory role of TOR in transcription of nutrient-responsive genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Powers, T. & Walter, P. Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol. Biol. Cell 10, 987–1000 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zaragoza, D., Ghavidel, A., Heitman, J. & Schultz, M. C. Rapamycin induces the G0 program of transcriptional repression in yeast by interfering with the TOR signaling pathway. Mol. Cell. Biol. 18, 4463–4470 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kamada, Y. et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507–1513 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Schmidt, A., Beck, T., Koller, A., Kunz, J. & Hall, M. N. The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J. 17, 6924–6931 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Beck, T., Schmidt, A. & Hall, M. N. Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast. J. Cell Biol. 146, 1227–1238 (1999).

    CAS  PubMed  PubMed Central  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).

    CAS  PubMed  Google Scholar 

  43. Shigemitsu, K. et al. Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways. Possible involvement of autophagy in cultured hepatoma cells. J. Biol. Chem. 274, 1058–1065 (1999).

    CAS  PubMed  Google Scholar 

  44. Edinger, A. L. & Thompson, C. B. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell 13, 2276–2288 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Beck, T. & Hall, M. N. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692 (1999).

    CAS  PubMed  Google Scholar 

  46. Komeili, A., Wedaman, K. P., O'Shea, E. K. & Powers, T. Mechanism of metabolic control. Target of rapamycin signaling links nitrogen quality to the activity of the rtg1 and rtg3 transcription factors. J. Cell Biol. 151, 863–878 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Crespo, J. L., Powers, T., Fowler, B. & Hall, M. N. The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine. Proc. Natl Acad. Sci. USA 99, 6784–6789 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shamji, A. F., Kuruvilla, F. G. & Schreiber, S. L. Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins. Curr. Biol. 10, 1574–1581 (2000).

    CAS  PubMed  Google Scholar 

  49. Dilova, I., Chen, C. Y. & Powers, T. Mks1 in concert with tor signaling negatively regulates RTG target gene expression in S. cerevisiae. Curr. Biol. 12, 389–395 (2002).

    CAS  PubMed  Google Scholar 

  50. Sekito, T., Liu, Z., Thornton, J. & Butow, R. A. RTG-dependent mitochondria-to-nucleus signaling is regulated by MKS1 and is linked to formation of yeast prion [URE3]. Mol. Biol. Cell 13, 795–804 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gingras, A. C., Raught, B. & Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 15, 807–826 (2001). An excellent review on mTOR signalling.

    CAS  PubMed  Google Scholar 

  54. Gingras, A. C. et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 15, 2852–2864 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Alessi, D. R., Kozlowski, M. T., Weng, Q. P., Morrice, N. & Avruch, J. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr. Biol. 8, 69–81 (1998).

    CAS  PubMed  Google Scholar 

  56. Pullen, N. et al. Phosphorylation and activation of p70s6k by PDK1. Science 279, 707–710 (1998).

    CAS  PubMed  Google Scholar 

  57. Tee, A. R. et al. Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl Acad. Sci. USA 99, 13571–13576 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Nave, B. T., Ouwens, M., Withers, D. J., Alessi, D. R. & Shepherd, P. R. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427–431 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sekulic, A. et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513 (2000).

    CAS  PubMed  Google Scholar 

  60. Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001).

    CAS  PubMed  Google Scholar 

  61. Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942–1945 (2001).

    CAS  PubMed  Google Scholar 

  62. Jaeschke, A. et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J. Cell Biol. 159, 217–224 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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). The first of several papers to suggest that mTOR responds to nutrients, amino acids in particular (see also references 64–66).

    CAS  PubMed  Google Scholar 

  64. 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  PubMed  PubMed Central  Google Scholar 

  65. Xu, G. et al. Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic β-cells. A possible role in protein translation and mitogenic signaling. J. Biol. Chem. 273, 28178–28184 (1998).

    CAS  PubMed  Google Scholar 

  66. Anthony, J. C. et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130, 2413–2419 (2000).

    CAS  PubMed  Google Scholar 

  67. Abraham, R. T. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 111, 9–12 (2002).

    CAS  PubMed  Google Scholar 

  68. McDaniel, M. L., Marshall, C. A., Pappan, K. L. & Kwon, G. Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic β-cells. Diabetes 51, 2877–2885 (2002). An interesting review on mTOR in β-cells. mTOR might control overall body growth in addition to autonomous cell growth.

    CAS  PubMed  Google Scholar 

  69. Goldberg, Y. Protein phosphatase 2A: who shall regulate the regulator? Biochem. Pharmacol. 57, 321–328 (1999).

    CAS  PubMed  Google Scholar 

  70. Luke, M. M. et al. The SAP, a new family of proteins, associate and function positively with the SIT4 phosphatase. Mol. Cell. Biol. 16, 2744–2755 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Sutton, A., Immanuel, D. & Arndt, K. T. The SIT4 protein phosphatase functions in late G1 for progression into S phase. Mol. Cell. Biol. 11, 2133–2148 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Como, C. J. & Arndt, K. T. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 10, 1904–1916 (1996). A thorough study that shows how phosphatase association with regulatory subunits is controlled by nutrients and TOR.

    CAS  PubMed  Google Scholar 

  73. Jiang, Y. & Broach, J. R. Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J. 18, 2782–2792 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Jacinto, E., Guo, B., Arndt, K. T., Schmelzle, T. & Hall, M. N. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol. Cell 8, 1017–1026 (2001).

    CAS  PubMed  Google Scholar 

  75. Peterson, R. T., Desai, B. N., Hardwick, J. S. & Schreiber, S. L. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin associated protein. Proc. Natl Acad. Sci. USA 96, 4438–4442 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Murata, K., Wu, J. & Brautigan, D. L. B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc. Natl Acad. Sci. USA 94, 10624–10629 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Inui, S. et al. Ig receptor binding protein 1 (α4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A. Blood 92, 539–546 (1998).

    CAS  PubMed  Google Scholar 

  78. Trockenbacher, A. et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nature Genet. 29, 287–294 (2001).

    CAS  PubMed  Google Scholar 

  79. Liu, J., Prickett, T. D., Elliott, E., Meroni, G. & Brautigan, D. L. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit α4. Proc. Natl Acad. Sci. USA 98, 6650–6655 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Chung, H., Nairn, A. C., Murata, K. & Brautigan, D. L. Mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the α4 subunit which promotes dephosphorylation of elongation factor-2. Biochemistry 38, 10371–10376 (1999).

    CAS  PubMed  Google Scholar 

  81. Saucedo, L. & Edgar, B. Why size matters: altering cell size. Curr. Opin. Genet. Dev. 12, 565–571 (2002).

    CAS  PubMed  Google Scholar 

  82. Bohni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875 (1999).

    CAS  PubMed  Google Scholar 

  83. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 15, 6584–6594 (1996). The first in a series of excellent papers on cell growth in Drosophila.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Rintelen, F., Stocker, H., Thomas, G. & Hafen, E. PDK1 regulates growth through Akt and S6K in Drosophila. Proc. Natl Acad. Sci. USA 98, 15020–15025 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nature Cell Biol. 1, 500–506 (1999).

    CAS  PubMed  Google Scholar 

  86. Montagne, J. et al. Drosophila S6 kinase: a regulator of cell size. Science 285, 2126–2129 (1999).

    CAS  PubMed  Google Scholar 

  87. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 13, 3244–3258 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Potter, C. J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).

    CAS  PubMed  Google Scholar 

  89. Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E. & Hariharan, I. K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001).

    CAS  PubMed  Google Scholar 

  90. Miron, M. et al. The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Nature Cell Biol. 3, 596–601 (2001).

    CAS  PubMed  Google Scholar 

  91. Rommel, C. et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nature Cell Biol. 3, 1009–1013 (2001).

    CAS  PubMed  Google Scholar 

  92. Bodine, S. C. et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nature Cell Biol. 3, 1014–1019 (2001). References 91 and 92 argue for a major role of the mTOR and Akt pathways in controlling overload-induced skeletal muscle hypertrophy.

    CAS  PubMed  Google Scholar 

  93. Musaro, A., McCullagh, K. J., Naya, F. J., Olson, E. N. & Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999).

    CAS  PubMed  Google Scholar 

  94. Semsarian, C. et al. Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway. Nature 400, 576–581 (1999).

    CAS  PubMed  Google Scholar 

  95. Pallafacchina, G., Calabria, E., Serrano, A. L., Kalhovde, J. M. & Schiaffino, S. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc. Natl Acad. Sci. USA 99, 9213–9218 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Reynolds, T. H., Bodine, S. C. & Lawrence, J. C. Jr. Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J. Biol. Chem. 277, 17657–17662 (2002).

    CAS  PubMed  Google Scholar 

  97. Baar, K. & Esser, K. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am. J. Physiol. 276, C120–C127 (1999).

    CAS  PubMed  Google Scholar 

  98. Shioi, T. et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Martin, K. C. et al. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938 (1997).

    CAS  PubMed  Google Scholar 

  100. Casadio, A. et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237 (1999).

    CAS  PubMed  Google Scholar 

  101. Tang, S. J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl Acad. Sci. USA 99, 467–472 (2002). References 100 and 101 show that TOR is involved in LTF and LTP.

    CAS  PubMed  Google Scholar 

  102. Takei, N., Kawamura, M., Hara, K., Yonezawa, K. & Nawa, H. Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin. J. Biol. Chem. 276, 42818–42825 (2001).

    CAS  PubMed  Google Scholar 

  103. Khan, A., Pepio, A. M. & Sossin, W. S. Serotonin activates S6 kinase in a rapamycin-sensitive manner in Aplysia synaptosomes. J. Neurosci. 21, 382–391 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Raymond, C. R., Redman, S. J. & Crouch, M. F. The phosphoinositide 3-kinase and p70 S6 kinase regulate long-term potentiation in hippocampal neurons. Neuroscience 109, 531–536 (2002).

    CAS  PubMed  Google Scholar 

  105. Abbott, M. A., Wells, D. G. & Fallon, J. R. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci. 19, 7300–7308 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Backman, S., Stambolic, V. & Mak, T. PTEN function in mammalian cell size regulation. Curr. Opin. Neurobiol. 12, 516–522 (2002).

    CAS  PubMed  Google Scholar 

  107. Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472–1487 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Pende, M. et al. Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408, 994–997 (2000).

    CAS  PubMed  Google Scholar 

  109. Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med. 8, 128–135 (2002).

    CAS  PubMed  Google Scholar 

  110. Huang, S. & Houghton, P. J. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr. Opin. Investig. Drugs 3, 295–304 (2002).

    CAS  PubMed  Google Scholar 

  111. Marx, S. O. & Marks, A. R. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 104, 852–855 (2001).

    CAS  PubMed  Google Scholar 

  112. Magasanik, B. & Kaiser, C. A. Nitrogen regulation in Saccharomyces cerevisiae. Gene 290, 1–18 (2002).

    CAS  PubMed  Google Scholar 

  113. Forsberg, H. & Ljungdahl, P. O. Sensors of extracellular nutrients in Saccharomyces cerevisiae. Curr. Genet. 40, 91–109 (2001).

    CAS  PubMed  Google Scholar 

  114. Rolland, F., Winderickx, J. & Thevelein, J. M. Glucose-sensing mechanisms in eukaryotic cells. Trends Biochem. Sci. 26, 310–317 (2001).

    CAS  PubMed  Google Scholar 

  115. Olson, E. N. & Williams, R. S. Calcineurin signaling and muscle remodeling. Cell 101, 689–692 (2000).

    CAS  PubMed  Google Scholar 

  116. Hawke, T. J. & Garry, D. J. Myogenic satellite cells: physiology to molecular biology. J. Appl. Physiol. 91, 534–551 (2001).

    CAS  PubMed  Google Scholar 

  117. Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Ruegg, T. Schmelzle, and K. Tatchell for their comments on the manuscript. This work was supported by grants from the Cancer Research Institute (E.J.), the Swiss National Science Foundation and the Canton of Basel (M.N.H.).

Author information

Authors and Affiliations

  1. Division of Biochemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, CH-4056, Switzerland

    Estela Jacinto & Michael N. Hall

Authors
  1. Estela Jacinto
    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.

Related links

Related links

DATABASES

Saccharomyces Genome Database

AVO1

AVO2

AVO3

KOG1

LST8

PPH21

PPH22

SIT4

TIP41

Swiss-Prot

4E-BP

CDC55

eIF4E

FKBP12

FRAP

GLN3

NPR1

PDK1

PTEN

raptor

RTG1

RTG3

TAP42

TSC1

TSC2

TOR1

TOR2

TPD3

FURTHER INFORMATION

Michael N. Hall's laboratory

Glossary

THE PHOSPHATIDYLINOSITOL KINASE (PIK)-RELATED PROTEIN KINASE FAMILY

(PIKK). A family of kinases that share sequence homology with lipid kinases but have a protein kinase activity. They are distinguished by the presence of a unique carboxy-terminal region (FATC) that is not present in the PIK family.

IMMUNOSUPPRESSANT

A drug or compound that inhibits an immune response through inhibition of T-cell growth and/or proliferation. It is used mainly to prevent rejection of organ grafts.

MACROLIDE

Any of several antibiotics that contain a lactone ring and are produced by Streptomyces sp.

UNDECAPEPTIDE

A peptide that is composed of a chain of 11 amino-acid residues.

IMMUNOPHILIN

An intracellular protein that binds immunosuppressive drugs.

STENT

A small, mesh-like tube made from stainless steel that is placed permanently inside an artery to hold it open to improve the flow of blood.

RESTENOSIS

A re-narrowing or blockage of an artery at the same site at which treatment, such as an angioplasty or stent procedure, has already taken place.

HEAT REPEATS

An amino-acid sequence motif that was first identified in huntingtin, elongation factor 3, regulatory A subunit of PP2A and TOR. Each repeat varies in length between 37 and 43 amino acids, occurs as anti-parallel α-helices, and is repeated tandemly at least three times in every protein. Most of the proteins that contain this motif are large, are known to be part of a complex and function in transport processes.

FAT DOMAIN

(FRAP, ATM, TRRAP). A domain spanning ∼500 amino acids that is found in the PIKK and TRRAP protein families. This domain is found amino-terminal to the kinase domain, and in combination with the FATC domain, which is found at the extreme carboxyl terminus. FAT and FATC domains are speculated to function in protein–protein interactions.

WD40 REPEAT

A repeat of ∼40 amino acids with a characteristic central Trp–Asp motif.

TRANSLATION INITIATION

The first step in protein synthesis, wherein the initiating ribosome scans along the messenger RNA and identifies the initiator codon to begin translation in the proper reading frame.

GATA-TYPE TRANSCRIPTION FACTORS

A family of transcription factors that contain a zinc-finger motif that was first identified in the vertebrate GATA-1 protein. These transcription factors bind the consensus sequence GATA in the 5′ non-coding regions of constitutive and inducible genes.

AMINO-ACID PERMEASE

A protein that transports amino acids from the outside to the inside of the cell. In yeast, these proteins contain 12 membrane-spanning segments, and are either broadly specific for a group of structurally related amino acids or highly specific for individual amino acids.

GLUCONEOGENESIS

The metabolic formation of carbohydrates from non-carbohydrate organic precursors.

RIBOSOMAL S6 PROTEIN KINASE

(S6K). A protein kinase that phosphorylates the ribosomal protein S6. S6 is involved in the translation of messenger RNA transcripts that contain a polypyrimidine tract at their transcriptional start site.

INITIATION FACTOR 4E-BINDING PROTEIN

(4E-BP; PHAS-I). When dephosphorylated, 4E-BP negatively regulates cap-dependent translation by binding and inhibiting the eukaryotic initiation factor 4E (eIF4E).

TSC COMPLEX

This consists of TSC1, a protein that is predicted to form coiled-coil structures and contains a putative transmembrane domain, and TSC2, a protein that contains a coiled-coil domain and a Rap GTPase-activating protein (GAP) domain. Mutations in either TSC1 or TSC2 are responsible for tuberous sclerosis, a genetic disorder that is characterized by hamartomas in various organs.

OPITZ SYNDROME

Opitz G/BBB syndrome is a congenital disorder that arises from defects in ventral midline development. Manifestations of this disorder include, among others, mental retardation, cleft lip and palate, and genitourinary defects.

UBIQUITIN LIGASE

An enzyme that couples the small protein ubiquitin to lysine residues on a target protein; it marks the target protein for destruction by the proteasome.

SATELLITE CELLS

Myogenic stem cells that are able to proliferate and form new myofibres.

LONG-TERM POTENTIATION

(LTP). LTP is a specific example of coincidence detection, whereby the high-frequency stimulation of a neuron increases the magnitude of subsequent responses, an effect that can last for days. LTP is believed to underlie some kinds of learning and memory.

SYNAPSE

The point of contact and transfer of information from one neuron to another.

RNA INTERFERENCE

(RNAi). The process by which an introduced double-stranded RNA specifically silences the expression of genes through degradation of their cognate messenger RNAs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacinto, E., Hall, M. TOR signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4, 117–126 (2003). https://doi.org/10.1038/nrm1018

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1018

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