Mammalian target of rapamycin

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FK506 binding protein 12-rapamycin associated protein 1
File:PBB Protein FRAP1 image.jpg
PDB rendering based on 1aue.
Available structures
PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB
Identifiers
Symbols FRAP1 ; FLJ44809; FRAP; FRAP2; MTOR; RAFT1; RAPT1
External IDs Template:OMIM5 Template:MGI HomoloGene: 3637
RNA expression pattern
File:PBB GE FRAP1 202288 at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
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The mammalian target of rapamycin, commonly known as mTOR, is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.[1][2]

Function

File:MTOR-pathway-betz.jpg
mTOR signaling pathway.[1]

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 possesses 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 threonine389.[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 threonine2446 and serine2448; events which appear to be stimulatory in regards to 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] However, unexpectedly mTORC2 also functions as the elusive "PDK2." mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at serine473, an event which stimulates Akt phosphorylation at threonine308 by PDK1 and leads to full Akt activation.[22][23]

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. It has also been shown that curcumin can inhibit the mTORC2-mediated phosphorylation of Akt/PKB at serine473, with subsequent loss of PDK1-mediated phosphorylation at threonine308.[2]

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.[24]

References

  1. ↑ 1.0 1.1 1.2 1.3 Hay N, Sonenberg N (2004). "Upstream and downstream of mTOR". Genes Dev. 18 (16): 1926–45. PMID 15314020.
  2. ↑ 2.0 2.1 2.2 2.3 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. 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. PMID 14684182.
  4. ↑ 4.0 4.1 Huang S, Houghton P (2001). "Mechanisms of resistance to rapamycins". Drug Resist Updat. 4 (6): 378–91. PMID 12030785.
  5. ↑ 5.0 5.1 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. PMID 16469695.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 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. PMID 12150925.
  8. ↑ 8.0 8.1 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. 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. 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. 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. PMID 11914378.
  12. ↑ 12.0 12.1 Pullen N, Thomas G (1997). "The modular phosphorylation and activation of p70s6k". FEBS Lett. 410 (1): 78–82. 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. PMID 9445476.
  14. ↑ Peterson R, Schreiber S (1998). "Translation control: connecting mitogens and the ribosome". Curr Biol. 8 (7): R248–50. 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. 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. 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. 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. PMID 10942774.
  19. ↑ 19.0 19.1 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. PMID 7935836.
  20. ↑ 20.0 20.1 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. PMID 16919458.
  21. ↑ 21.0 21.1 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. PMID 15268862.
  22. ↑ 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. 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. PMID 9445477.
  24. ↑ ""AKT, ILGF & Wnt pathways" at healthvalue.net". Retrieved 2007-07-12.

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

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