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MTOR 

FK506 binding protein 12-rapamycin associated protein 1
PDB rendering based on 1aue.
Available structures: 1aue, 1fap, 1nsg, 2fap, 2gaq, 3fap, 4fap
Identifiers
Symbols FRAP1; FLJ44809; FRAP; FRAP2; MTOR; RAFT1; RAPT1
External IDs OMIM: 601231 MGI: 1928394 HomoloGene: 3637
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 2475 56717
Ensembl ENSG00000198793 ENSMUSG00000028991
Uniprot P42345 Q3T9E1
Refseq NM_004958 (mRNA)
NP_004949 (protein)		 XM_622902 (mRNA)
XP_622902 (protein)
Location Chr 1: 11.09 - 11.25 Mb Chr 4: 147.29 - 147.4 Mb
Pubmed search [2] [3]

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.[1][2]

Contents

Function

Current research indicates that mTOR integrates the input from multiple upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and mitogens.[1] mTOR also functions as a sensor of cellular nutrient and energy levels and redox status.[3] The dysregulation of the mTOR pathway is implicated as a contributing factor to various human disease processes, especially various types of cancer.[2] Rapamycin is a bacterial natural product that can inhibit mTOR through association with its intracellular receptor FKBP12.[4][5] The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.[5]

mTOR has been shown to function as the catalytic subunit of two distinct molecular complexes in cells.[6]

Complexes

mTORC1

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory associated protein of mTOR (Raptor), and mammalian LST8/G-protein β-subunit like protein (mLST8/GβL).[7][8] This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis.[7][1] The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.[7][9]

mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin.[7][10][2] The two best characterized targets of mTORC1 are p70-S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).[1]

mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine residue.[11][12] This event stimulates the subsequent phosphorylation of S6K1 by PDK1.[12][13] Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome) and other components of the translational machinery.[14] S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites; phosphorylation at these sites appears to stimulate mTOR activity.[15][16]

mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner.[17][4][18] Non-phosphorylated 4E-BP1 binds tightly to the translation initiation factor eIF4E, preventing it from binding to 5'-capped mRNAs and recruiting them to the ribosomal initiation complex.[19] Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function.[19] The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL.[7][8] Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain.[7] When stimulatory signals are sensed, such as high nutrient/energy levels, the mTOR-Raptor C-terminal interaction is weakened and possibly completely lost, allowing mTOR kinase activity to be turned on. When stimulatory signals are withdrawn, such as low nutrient levels, the mTOR-Raptor C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR .[7]

mTORC2

mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).[20][21] mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[21] mTORC2 also appears to possess the activity of a previously elusive protein known as "PDK2." mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine residue by PDK1 and leads to full Akt activation[22][23]; curcumin inhibits both by preventing phosphorylation of the serine.[2]

mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.[20] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.[22] However, subsequent studies have shown that chronic exposure to rapamycin, while not effecting pre-existing mTORC2s, can bind to free mTOR molecules, thus inhibiting the formation of new mTORC2.[24]

Aging

mTOR signaling pathway.[1]
mTOR signaling pathway.[1]

Decreased TOR activity has been found to slow aging in Saccharomcyes cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster [25][26][27][28]. The NIA Interventions Testing Program is currently testing the mTOR inhibitor rapamycin to determine whether it increases lifespan in mice.

Kaeberlein and colleagues have proposed the hypothesis that decreased TOR activity accounts for lifespan extension by caloric restriction [29].

mTOR inhibitors as therapies

mTOR inhibitors are already used in the treatment of transplant rejection . They are also beginning to be used in the treatment of cancer.[30].

mTOR inhibitors may also be useful for treating several age-associated diseases.

References

  1. ^ a b c d Hay N, Sonenberg N (2004). "Upstream and downstream of mTOR". Genes Dev 18 (16): 1926–45. doi:10.1101/gad.1212704. PMID 15314020. 
  2. ^ a b c d Beevers C, Li F, Liu L, Huang S (2006). "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells". Int J Cancer 119 (4): 757–64. doi:10.1002/ijc.21932. PMID 16550606. 
  3. ^ Tokunaga C, Yoshino K, Yonezawa K (2004). "mTOR integrates amino acid- and energy-sensing pathways". Biochem Biophys Res Commun 313 (2): 443–6. doi:10.1016/j.bbrc.2003.07.019. PMID 14684182. 
  4. ^ a b Huang S, Houghton P (2001). "Mechanisms of resistance to rapamycins". Drug Resist Updat 4 (6): 378–91. doi:10.1054/drup.2002.0227. PMID 12030785. 
  5. ^ a b Huang S, Bjornsti M, Houghton P (2003). "Rapamycins: mechanism of action and cellular resistance". Cancer Biol Ther 2 (3): 222–32. PMID 12878853. 
  6. ^ Wullschleger S, Loewith R, Hall M (2006). "TOR signaling in growth and metabolism". Cell 124 (3): 471–84. doi:10.1016/j.cell.2006.01.016. PMID 16469695. 
  7. ^ a b c d e f g Kim D, Sarbassov D, Ali S, King J, Latek R, Erdjument-Bromage H, Tempst P, Sabatini D (2002). "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell 110 (2): 163–75. doi:10.1016/S0092-8674(02)00808-5. PMID 12150925. 
  8. ^ a b Kim D, Sarbassov D, Ali S, Latek R, Guntur K, Erdjument-Bromage H, Tempst P, Sabatini D (2003). "GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR". Mol Cell 11 (4): 895–904. doi:10.1016/S1097-2765(03)00114-X. PMID 12718876. 
  9. ^ Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001). "Phosphatidic acid-mediated mitogenic activation of mTOR signaling". Science 294 (5548): 1942–5. doi:10.1126/science.1066015. PMID 11729323. 
  10. ^ McMahon L, Yue W, Santen R, Lawrence J (2005). "Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex". Mol Endocrinol 19 (1): 175–83. doi:10.1210/me.2004-0305. PMID 15459249. 
  11. ^ Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis P, Thomas G (2002). "Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site". J Biol Chem 277 (22): 20104–12. doi:10.1074/jbc.M201745200. PMID 11914378. 
  12. ^ a b Pullen N, Thomas G (1997). "The modular phosphorylation and activation of p70s6k". FEBS Lett 410 (1): 78–82. doi:10.1016/S0014-5793(97)00323-2. PMID 9247127. 
  13. ^ Pullen N, Dennis P, Andjelkovic M, Dufner A, Kozma S, Hemmings B, Thomas G (1998). "Phosphorylation and activation of p70s6k by PDK1". Science 279 (5351): 707–10. doi:10.1126/science.279.5351.707. PMID 9445476. 
  14. ^ Peterson R, Schreiber S (1998). "Translation control: connecting mitogens and the ribosome". Curr Biol 8 (7): R248–50. doi:10.1016/S0960-9822(98)70152-6. PMID 9545190. 
  15. ^ Chiang G, Abraham R (2005). "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". J Biol Chem 280 (27): 25485–90. doi:10.1074/jbc.M501707200. PMID 15899889. 
  16. ^ Holz M, Blenis J (2005). "Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase". J Biol Chem 280 (28): 26089–93. doi:10.1074/jbc.M504045200. PMID 15905173. 
  17. ^ Gingras A, Gygi S, Raught B, Polakiewicz R, Abraham R, Hoekstra M, Aebersold R, Sonenberg N (1999). "Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism". Genes Dev 13 (11): 1422–37. doi:10.1101/gad.13.11.1422. PMID 10364159. 
  18. ^ Mothe-Satney I, Brunn G, McMahon L, Capaldo C, Abraham R, Lawrence J (2000). "Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies". J Biol Chem 275 (43): 33836–43. doi:10.1074/jbc.M006005200. PMID 10942774. 
  19. ^ a b Pause A, Belsham G, Gingras A, Donzé O, Lin T, Lawrence J, Sonenberg N (1994). "Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function". Nature 371 (6500): 762–7. doi:10.1038/371762a0. PMID 7935836. 
  20. ^ a b Frias M, Thoreen C, Jaffe J, Schroder W, Sculley T, Carr S, Sabatini D (2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Curr Biol 16 (18): 1865–70. doi:10.1016/j.cub.2006.08.001. PMID 16919458. 
  21. ^ a b Sarbassov D, Ali S, Kim D, Guertin D, Latek R, Erdjument-Bromage H, Tempst P, Sabatini D (2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Curr Biol 14 (14): 1296–302. doi:10.1016/j.cub.2004.06.054. PMID 15268862. 
  22. ^ a b Sarbassov D, Guertin D, Ali S, Sabatini D (2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470. 
  23. ^ Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter G, Holmes A, Gaffney P, Reese C, McCormick F, Tempst P, Coadwell J, Hawkins P (1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B". Science 279 (5351): 710–4. doi:10.1126/science.279.5351.710. PMID 9445477. 
  24. ^ Sarbassov D, Ali S, Sengupta S, Sheen J, Hsu P, Bagley A, Markhard A, Sabatini D (2006). "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Mol Cell 22 (2): 159–68. doi:10.1016/j.molcel.2006.03.029. PMID 16603397. 
  25. ^ Kaeberlein, M., Powers, R.W., 3rd, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., and Kennedy, B.K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196.
  26. ^ Powers, R.W., 3rd, Kaeberlein, M., Caldwell, S.D., Kennedy, B.K., and Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20, 174-184.
  27. ^ Jia, K., Chen, D., and Riddle, D.L. (2004). The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897-3906.
  28. ^ Kapahi, P., Zid, B.M., Harper, T., Koslover, D., Sapin, V., and Benzer, S. (2004). Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14, 885-890.
  29. ^ Kaeberlein, M., Powers, R.W., 3rd, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., and Kennedy, B.K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196.
  30. ^ Easton et al. (2006). "mTOR and cancer therapy". Oncogene 25 (48): 6436–46. doi:10.1038/sj.onc.1209886. 

Further reading

  • Huang S, Houghton PJ (2002). "Mechanisms of resistance to rapamycins". Drug Resist. Updat. 4 (6): 378–91. doi:10.1054/drup.2002.0227. PMID 12030785. 
  • Harris TE, Lawrence JC (2004). "TOR signaling". Sci. STKE 2003 (212): re15. doi:10.1126/stke.2122003re15. PMID 14668532. 
  • Easton JB, Houghton PJ (2005). "Therapeutic potential of target of rapamycin inhibitors". Expert Opin. Ther. Targets 8 (6): 551–64. doi:10.1517/14728222.8.6.551. PMID 15584862. 
  • Deldicque L, Theisen D, Francaux M (2005). "Regulation of mTOR by amino acids and resistance exercise in skeletal muscle". Eur. J. Appl. Physiol. 94 (1-2): 1–10. doi:10.1007/s00421-004-1255-6. PMID 15702344. 
  • Weimbs T (2007). "Regulation of mTOR by polycystin-1: is polycystic kidney disease a case of futile repair?". Cell Cycle 5 (21): 2425–9. PMID 17102641. 
  • Sun SY, Fu H, Khuri FR (2007). "Targeting mTOR signaling for lung cancer therapy". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1 (2): 109–11. PMID 17409838. 
  • Abraham RT, Gibbons JJ (2007). "The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy". Clin. Cancer Res. 13 (11): 3109–14. doi:10.1158/1078-0432.CCR-06-2798. PMID 17545512. 

External links

v • d • e
Kinases: Serine/threonine-specific protein kinases (primarily EC 2.7.11)
2.7.11
2.7.12
MAP2K (1, 2, 3, 4, 5, 6, 7)
2.7.1.37, or unknown
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