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mTOR: from growth signal integration to cancer, diabetes and ageing

Key Points

  • The mammalian target of rapamycin (mTOR) is a highly conserved kinase that belongs to the phosphoinositide 3-kinase-related protein kinases (PIKK) family. mTOR participates in two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2.

  • mTORC1 integrates energy, nutrients, stress and growth factors and, in response to these stimuli, it drives the growth of cells, organs and whole organisms. mTORC2, which is activated by growth factors, promotes cell proliferation and survival.

  • mTOR signalling maximizes energy storage and consumption. Upon chronic activation, mTORC1 drives insulin resistance by suppressing insulin receptor signalling and promoting fat accumulation.

  • mTORC1 and mTORC2 are tightly linked with signalling pathways that lead to cancer. mTORC1 drives tumorigenesis by boosting translation of oncogenes, promoting anabolism and angiogenesis and suppressing autophagy. mTORC2 activates Akt and other AGC family kinases that promote cell proliferation and survival. Therapeutic strategies that are based on novel catalytic mTOR inhibitors have shown promising preclinical results.

  • Our increasing knowledge of the molecular mechanisms underlying ageing is revealing a major role for mTOR in this process. Thus, understanding mTORC1 and mTORC2 biology is crucial for the development of novel drugs that can stave off ageing and age-related diseases.

Abstract

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.

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Figure 1: Domain organization of mTOR and mTORC proteins.
Figure 2: The mTOR signalling pathway.
Figure 3: mTOR in metabolism.
Figure 4: mTOR in cancer.
Figure 5: mTOR in ageing.

References

  1. 1

    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  Google Scholar 

  2. 2

    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  Google Scholar 

  3. 3

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

    CAS  Google Scholar 

  4. 4

    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 

  5. 5

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    CAS  PubMed  Google Scholar 

  8. 8

    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).

    CAS  PubMed  Google Scholar 

  9. 9

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

    CAS  PubMed  Google Scholar 

  10. 10

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

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

    CAS  Google Scholar 

  12. 12

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    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. Nature Cell Biol. 9, 316–323 (2007).

    CAS  Google Scholar 

  14. 14

    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).

    CAS  Google Scholar 

  15. 15

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    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).

    CAS  PubMed  Google Scholar 

  17. 17

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

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

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

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

    CAS  PubMed  Google Scholar 

  20. 20

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

    CAS  PubMed  Google Scholar 

  21. 21

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

    Google Scholar 

  22. 22

    Haghighat, A., Mader, S., Pause, A. & Sonenberg, N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 14, 5701–5709 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

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

    CAS  PubMed  Google Scholar 

  24. 24

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

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    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). This study describes the function of SKAR as a scaffold that recruits S6K1 to newly synthesized mRNAs.

    CAS  Google Scholar 

  26. 26

    Wilson, K. F., Wu, W. J. & Cerione, R. A. Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex. J. Biol. Chem. 275, 37307–37310 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

    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). This article describes the physical association of mTORC1 with untranslated mRNAs through its interaction with eIF3.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

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

    CAS  Google Scholar 

  30. 30

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

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Claypool, J. A. et al. Tor pathway regulates Rrn3p-dependent recruitment of yeast RNA polymerase I to the promoter but does not participate in alteration of the number of active genes. Mol. Biol. Cell 15, 946–956 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Martin, D. E., Soulard, A. & Hall, M. N. TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1. Cell 119, 969–979 (2004).

    CAS  PubMed  Google Scholar 

  33. 33

    Schawalder, S. B. et al. Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. Nature 432, 1058–1061 (2004).

    CAS  PubMed  Google Scholar 

  34. 34

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

    CAS  Google Scholar 

  35. 35

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    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 

  37. 37

    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  PubMed  PubMed Central  Google Scholar 

  38. 38

    Hosokawa, N. et al. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5, 973–979 (2009).

    CAS  PubMed  Google Scholar 

  39. 39

    Kamada, Y. et al. Tor2 directly phosphorylates the AGC kinase Ypk2 to regulate actin polarization. Mol. Cell Biol. 25, 7239–7248 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Schmidt, A., Bickle, M., Beck, T. & Hall, M. N. The yeast phosphatidylinositol kinase homolog TOR2 activates RHO1 and RHO2 via the exchange factor ROM2. Cell 88, 531–542 (1997).

    CAS  PubMed  Google Scholar 

  41. 41

    Facchinetti, V. et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J. 27, 1932–1943 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    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).

    CAS  PubMed  Google Scholar 

  43. 43

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

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    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). References 42–44 show that mTORC2 mediates the phosphorylation and activation of AGC family kinases.

    CAS  Google Scholar 

  45. 45

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

    CAS  Google Scholar 

  46. 46

    Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    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  PubMed  Google Scholar 

  48. 48

    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 

  49. 49

    Christie, G. R., Hajduch, E., Hundal, H. S., Proud, C. G. & Taylor, P. M. Intracellular sensing of amino acids in Xenopus laevis oocytes stimulates p70 S6 kinase in a target of rapamycin-dependent manner. J. Biol. Chem. 277, 9952–9957 (2002).

    CAS  PubMed  Google Scholar 

  50. 50

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Findlay, G. M., Yan, L., Procter, J., Mieulet, V. & Lamb, R. F. A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem. J. 403, 13–20 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yan, L. et al. PP2AT61ɛ is an inhibitor of MAP4K3 in nutrient signaling to mTOR. Mol. Cell 37, 633–642 (2010).

    CAS  PubMed  Google Scholar 

  53. 53

    Gulati, P. et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab. 7, 456–465 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Nobukuni, T. et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl Acad. Sci. USA 102, 14238–14243 (2005).

    CAS  PubMed  Google Scholar 

  55. 55

    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). References 10 and 55 describe the identification of the Rag GTPases as key mediators of amino acid signalling to mTORC1. Reference 10 also shows that amino acids regulate the subcellular localization of mTOR.

    CAS  PubMed  Google Scholar 

  56. 56

    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  PubMed  PubMed Central  Google Scholar 

  57. 57

    Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566–571 (2003).

    CAS  PubMed  Google Scholar 

  58. 58

    Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature Cell Biol. 5, 559–565 (2003).

    CAS  PubMed  Google Scholar 

  59. 59

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

    CAS  PubMed  Google Scholar 

  60. 60

    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).

    CAS  PubMed  Google Scholar 

  61. 61

    Zurita-Martinez, S. A., Puria, R., Pan, X., Boeke, J. D. & Cardenas, M. E. Efficient Tor signaling requires a functional class C Vps protein complex in Saccharomyces cerevisiae. Genetics 176, 2139–2150 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

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

    CAS  PubMed  Google Scholar 

  63. 63

    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 

  64. 64

    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).

    CAS  PubMed  Google Scholar 

  65. 65

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

    CAS  Google Scholar 

  66. 66

    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).

    CAS  PubMed  Google Scholar 

  67. 67

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).

    CAS  PubMed  Google Scholar 

  69. 69

    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).

    CAS  PubMed  Google Scholar 

  70. 70

    Kovacina, K. S. et al. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 278, 10189–10194 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    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).

    CAS  PubMed  Google Scholar 

  72. 72

    Castilho, R. M., Squarize, C. H., Chodosh, L. A., Williams, B. O. & Gutkind, J. S. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 5, 279–289 (2009). This study shows that Wnt-induced hyperproliferation of epidermal stem cells requires mTORC1.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    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). This article describes a crosstalk between Wnt and mTORC1 that is mediated by GSK3β-dependent phosphorylation of TSC2.

    CAS  PubMed  Google Scholar 

  74. 74

    Gangloff, Y. G. et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell Biol. 24, 9508–9516 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Murakami, M. et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol. Cell Biol. 24, 6710–6718 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

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

    CAS  Google Scholar 

  77. 77

    Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007).

    CAS  Google Scholar 

  78. 78

    Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev. 18, 1533–1538 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008). This study reports that AMPK directly inhibits mTORC1 by phosphorylating RAPTOR to induce its association with 14-3-3 proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Reiling, J. H. & Hafen, E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879–2892 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Feng, Z. et al. The regulation of AMPK β1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1–AKT–mTOR pathways. Cancer Res. 67, 3043–3053 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    CAS  Google Scholar 

  85. 85

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Charest, P. G. et al. A Ras signaling complex controls the RasC–TORC2 pathway and directed cell migration. Dev. Cell 18, 737–749 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Lee, S. et al. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 16, 4572–4583 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    He, C. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

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

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009). This study shows that 4E-BP1 is upregulated on DR in D. melanogaster and enhances mitochondrial function and lifespan.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

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

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008).

    CAS  PubMed  Google Scholar 

  96. 96

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

    CAS  PubMed  Google Scholar 

  97. 97

    Yeh, W. C., Bierer, B. E. & McKnight, S. L. Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells. Proc. Natl Acad. Sci. USA 92, 11086–11090 (1995).

    CAS  PubMed  Google Scholar 

  98. 98

    Gagnon, A., Lau, S. & Sorisky, A. Rapamycin-sensitive phase of 3T3-L1 preadipocyte differentiation after clonal expansion. J. Cell. Physiol. 189, 14–22 (2001).

    CAS  PubMed  Google Scholar 

  99. 99

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

    CAS  PubMed  Google Scholar 

  100. 100

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

    CAS  PubMed  Google Scholar 

  101. 101

    Le Bacquer, O. et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J. Clin. Invest. 117, 387–396 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Kim, J. B. & Spiegelman, B. M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 10, 1096–1107 (1996).

    CAS  PubMed  Google Scholar 

  103. 103

    Kim, J. B., Wright, H. M., Wright, M. & Spiegelman, B. M. ADD1/SREBP1 activates PPARγ through the production of endogenous ligand. Proc. Natl Acad. Sci. USA 95, 4333–4337 (1998).

    CAS  PubMed  Google Scholar 

  104. 104

    Zhang, H. H. et al. Insulin stimulates adipogenesis through the Akt–TSC2–mTORC1 pathway. PLoS ONE 4, e6189 (2009).

    PubMed  PubMed Central  Google Scholar 

  105. 105

    Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008). This report shows that SREBP is a key mediator of growth by promoting lipogenesis downstream of PI3K–Akt–mTORC1.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Dowell, P., Otto, T. C., Adi, S. & Lane, M. D. Convergence of peroxisome proliferator-activated receptor γ and Foxo1 signaling pathways. J. Biol. Chem. 278, 45485–45491 (2003).

    CAS  PubMed  Google Scholar 

  107. 107

    Nakae, J. et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119–129 (2003).

    CAS  PubMed  Google Scholar 

  108. 108

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

    CAS  Google Scholar 

  109. 109

    Nakae, J., Kitamura, T., Silver, D. L. & Accili, D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J. Clin. Invest. 108, 1359–1367 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

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

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

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

    CAS  Google Scholar 

  112. 112

    Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006).

    CAS  Google Scholar 

  114. 114

    Yuan, T. L. & Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–5510 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

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

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Wendel, H. G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Wendel, H. G. et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 21, 3232–3237 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Petroulakis, E. et al. p53-dependent translational control of senescence and transformation via 4E-BPs. Cancer Cell 16, 439–446 (2009). References 116–119 demonstrate a key role for 4E-BP1-mediated translational control in the proliferation and survival of cancer cells.

    CAS  PubMed  Google Scholar 

  120. 120

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763–777 (2007).

    CAS  PubMed  Google Scholar 

  122. 122

    Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Marino, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573–18583 (2007).

    CAS  PubMed  Google Scholar 

  125. 125

    Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006).

    CAS  PubMed  Google Scholar 

  126. 126

    Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    CAS  PubMed  Google Scholar 

  127. 127

    Guertin, D. A. et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15, 148–159 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Hietakangas, V. & Cohen, S. M. TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer 8, 282 (2008).

    PubMed  PubMed Central  Google Scholar 

  129. 129

    Hoang, B. et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 116, 4560–4568 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Masri, J. et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 67, 11712–11720 (2007).

    CAS  PubMed  Google Scholar 

  131. 131

    O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065–3074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Zhang, H. et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J. Clin. Invest. 117, 730–738 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Efeyan, A. & Sabatini, D. M. mTOR and cancer: many loops in one pathway. Curr. Opin. Cell Biol. 22, 169–176 (2010).

    CAS  PubMed  Google Scholar 

  135. 135

    Shor, B. et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res. 68, 2934–2943 (2008).

    CAS  PubMed  Google Scholar 

  136. 136

    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).

    CAS  Google Scholar 

  137. 137

    McMahon, L. P., Choi, K. M., Lin, T. A., Abraham, R. T. & Lawrence, J. C. Jr. The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol. Cell Biol. 22, 7428–7438 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

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

    Google Scholar 

  139. 139

    Chresta, C. M. et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70, 288–298 (2010).

    CAS  PubMed  Google Scholar 

  140. 140

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

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Yu, K. et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 69, 6232–6240 (2009). References 35 and 138–141 report the synthesis of catalytic inhibitors of mTOR.

    CAS  PubMed  Google Scholar 

  142. 142

    Nardella, C. et al. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci. Signal. 2, ra2 (2009).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Janes, M. R. et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Med. 16, 205–213 (2010). This study details the efficacy of mTOR catalytic inhibitors in mouse and human models of leukaemia.

    CAS  Google Scholar 

  144. 144

    Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 1351–1356 (2008).

    CAS  PubMed  Google Scholar 

  145. 145

    Fan, Q. W. et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341–349 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Liu, T. J. et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol. Cancer Ther. 8, 2204–2210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Brachmann, S. M. et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc. Natl Acad. Sci. USA 106, 22299–22304 (2009).

    CAS  PubMed  Google Scholar 

  148. 148

    Chiarini, F. et al. Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res. 69, 3520–3528 (2009).

    CAS  PubMed  Google Scholar 

  149. 149

    Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).

    CAS  PubMed  Google Scholar 

  150. 150

    Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).

    CAS  Google Scholar 

  151. 151

    Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005). This article provides evidence that reducing the activity of the TOR pathway extends the lifespan of S. cerevisiae and that DR acts through TOR.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

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

    CAS  PubMed  Google Scholar 

  153. 153

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

    CAS  Google Scholar 

  154. 154

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

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

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). The first report that mTOR inhibition has beneficial effects on the lifespan of mammals.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

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

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

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

    CAS  Google Scholar 

  159. 159

    Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Steffen, K. K. et al. Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 133, 292–302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445, 922–926 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).

    CAS  Google Scholar 

  163. 163

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

    PubMed  PubMed Central  Google Scholar 

  164. 164

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

    CAS  Google Scholar 

  165. 165

    Zhang, C. & Cuervo, A. M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nature Med. 14, 959–965 (2008).

    CAS  PubMed  Google Scholar 

  166. 166

    Wei, M. et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 4, e13 (2008).

    PubMed  PubMed Central  Google Scholar 

  167. 167

    He, S., Nakada, D. & Morrison, S. J. Mechanisms of stem cell self-renewal. Annu. Rev. Cell Dev. Biol. 25, 377–406 (2009).

    CAS  PubMed  Google Scholar 

  168. 168

    Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    CAS  PubMed  Google Scholar 

  169. 169

    Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

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

    PubMed  PubMed Central  Google Scholar 

  171. 171

    Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

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

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Flinn, R. J. & Backer, J. M. mTORC1 signals from late endosomes: taking a TOR of the endocytic system. Cell Cycle 9, 1869–1870 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Li, L., Edgar, B. A. & Grewal, S. S. Nutritional control of gene expression in Drosophila larvae via TOR, Myc and a novel cis-regulatory element. BMC Cell Biol. 11, 7 (2010).

    PubMed  PubMed Central  Google Scholar 

  175. 175

    Berchtold, D. & Walther, T. C. TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol. Biol. Cell 20, 1565–1575 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge support from the US National Institutes of Health, the Howard Hughes Medical Institute and the Whitehead Institute for Biomedical Research. R.Z. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. A.E. is supported by a Human Frontier Science Program postdoctoral fellowship.

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Glossary

Macrolide

A naturally occurring drug, generally an antibiotic, that is composed of a large lactone carbon ring.

WD40 domain

A protein domain that comprises a 40-amino-acid- long protein motif that contains a Trp–Asp (W–D) dipeptide at its carboxyl terminus. Several WD40 repeats are often arranged in a β-propeller configuration, forming a protein–protein interaction surface.

DEP domain

(Dishevelled, EGL-10 and pleckstrin domain). A domain of unknown function that is present in signalling proteins.

PDZ domain

(Postsynaptic density of 95 kDa, Discs large and zona occludens 1 domain). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.

Autophagosome

A transient membrane vesicle that engulfs and digests cellular components.

Guanine nucleotide exchange factor

(GEF). A protein that promotes the loading of GTP onto G proteins, resulting in their activation.

Anabolism

A set of chemical reactions that build complex molecules from simpler units, consuming energy in the process.

GTPase activating protein

(GAP). A protein that promotes hydrolysis of GTP to GDP by G proteins, resulting in their inactivation.

β-oxidation

The breakdown of fatty acids that occurs in the mitochondria and generates acetyl CoA, which is the entry substrate for the tricarboxylic acid cycle.

Triglyceride

A lipid that is formed by the esterification of fatty acids with glycerol. Triglycerides are the most abundant form of lipid storage.

Gluconeogenesis

The chain of enzymatic reactions, mainly occurring in the liver, which leads to the de novo production of glucose from more simple carbon precursors and ATP.

Senescence

An almost irreversible stage of permanent G0–G1 cell-cycle arrest that is linked to morphological changes, metabolic changes and changes in gene expression (for example, of the gene encoding β-galactosidase).

Quiescence

Cells in this state have exited the cell cycle and are in the G0 ('resting') phase, but can re-enter the cell cycle.

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Zoncu, R., Efeyan, A. & Sabatini, D. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21–35 (2011). https://doi.org/10.1038/nrm3025

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