Mammalian target of rapamycin
FK506 binding protein 12-rapamycin associated protein 1
|PDB rendering based on 1aue.|
|Available structures:, , , , , ,|
|RNA expression pattern|
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.
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. mTOR also functions as a sensor of cellular nutrient and energy levels and redox status. The dysregulation of the mTOR pathway is implicated as a contributing factor to various human disease processes, especially various types of cancer. Rapamycin is a bacterial natural product that can inhibit mTOR through association with its intracellular receptor FKBP12. The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.
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). This complex possesses the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis. The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin. The two best characterized targets of mTORC1 are p70-S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).
mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on threonine389. This event stimulates the subsequent phosphorylation of S6K1 by PDK1. 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. 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.
mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner. 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. Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function. The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL. Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain. 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 .
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). 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). 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.
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels. Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.Cite error: Closing </ref> missing for <ref> tag 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.
mTOR inhibitors as therapies
- ↑ 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.
- ↑ 2.0 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.
- ↑ 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.
- ↑ 4.0 4.1 Huang S, Houghton P (2001). "Mechanisms of resistance to rapamycins". Drug Resist Updat 4 (6): 378-91. PMID 12030785.
- ↑ 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.
- ↑ Wullschleger S, Loewith R, Hall M (2006). "TOR signaling in growth and metabolism". Cell 124 (3): 471-84. PMID 16469695.
- ↑ 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.
- ↑ 8.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 12.0 12.1 Pullen N, Thomas G (1997). "The modular phosphorylation and activation of p70s6k". FEBS Lett 410 (1): 78-82. PMID 9247127.
- ↑ 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.
- ↑ Peterson R, Schreiber S (1998). "Translation control: connecting mitogens and the ribosome". Curr Biol 8 (7): R248-50. PMID 9545190.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 19.0 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.
- ↑ 20.0 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.
- ↑ 21.0 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.
- ↑ 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.
- ↑ 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.
- ↑ "AKT, ILGF & Wnt pathways" at healthvalue.net. Retrieved on 2007-07-12.
- 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:10.1517/14728188.8.131.521. 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.
Kinases: Serine/threonine-specific protein kinases (primarily EC 2.7.11)
|2.7.11||Pyruvate dehydrogenase kinase - Protein kinase A - Protein kinase G - Protein kinase C (Protein kinase Mζ) - Rhodopsin - Beta adrenergic receptor - G-protein coupled receptor kinases - Ca2+/calmodulin-dependent - Myosin light-chain) - Phosphorylase - Cyclin-dependent - Mitogen-activated (Extracellular signal-regulated, C-Jun N-terminal (MAPK8, MAPK9), P38 mitogen-activated protein) - MAP3K - GSK-3 - AMP-activated|
|2.7.12||MAP2K (1, 2, 3, 4, 5, 6, 7)|
|184.108.40.206, or unknown||Anti-Mullerian hormone receptor - Ataxia telangiectasia mutated - Aurora (A, B) - Mammalian target of rapamycin - Bone morphogenetic protein receptors (1, 2) - CDKL5 - c-Raf - EIF-2 - Ribosomal s6 - Protein kinase B - PDK1|
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