Mammalian target of rapamycin

Mechanistic target of rapamycin (serine/threonine kinase)

PDB rendering based on 1aue.
Identifiers
Symbols MTOR; FLJ44809; FRAP; FRAP1; FRAP2; RAFT1; RAPT1
External IDs OMIM: 601231 MGI: 1928394 HomoloGene: 3637 GeneCards: MTOR Gene
EC number 2.7.11.1
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 2475 56717
Ensembl ENSG00000198793 ENSMUSG00000028991
UniProt P42345 Q3T9E1
RefSeq (mRNA) NM_004958.3 NM_020009.2
RefSeq (protein) NP_004949.1 NP_064393.2
Location (UCSC) Chr 1:
11.17 – 11.32 Mb		 Chr 4:
147.82 – 147.93 Mb
PubMed search [2] [3]

The mammalian target of rapamycin (mTOR) also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) is a protein which in humans is encoded by the FRAP1 gene.[1][2] mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.[3][4] mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Contents

Function

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.[3] mTOR also senses cellular nutrient and energy levels and redox status.[5] The mTOR pathway is dysregulated in human diseases, especially certain cancers.[4] Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12.[6][7] The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.[7]

mTOR is the catalytic subunit of two molecular complexes.[8]

mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that Tor was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2.

Complexes

mTORC1

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian LST8/G-protein β-subunit like protein (mLST8/GβL) and the recently identified partners PRAS40 and DEPTOR.[9][10] This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis.[3][9] The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.[9][11]

mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, rapamycin, and farnesylthiosalicylic acid (FTS).[9][12] The two best characterized targets of mTORC1 are p70-S6 Kinase 1 (S6K1) and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1.[3]

mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine residue (T389) .[13][14] This event stimulates the subsequent phosphorylation of S6K1 by PDK1.[14][15] 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.[16] 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.[17][18]

mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner.[6][19][20] 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.[21] Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function.[21] The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL.[9][10] Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain.[9] 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 .[9]

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).[22][23] 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).[23] 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 S473 . Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation;[24][25] curcumin inhibits both by preventing phosphorylation of the serine.[4]

mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.[22] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.[24] However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2.[26]

Physiological significance (KO phenotypes)

The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Therefore, performing knockout experiments is a good way to shed light on more specific molecules and their roles in this pathway. Protein function inhibition using knockdowns and knockouts were found to produce the following phenotypes:

Aging

Decreased TOR activity has been found to slow aging in S. cerevisiae, C. elegans, and D. melanogaster.[32][33][34][35] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[36]

It's hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[32][33] But infusion of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[37]

mTOR inhibitors as therapies

mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection. Rapamycin is also related to the therapy of glycogen storage disease (GSD). Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS(glycogen storage) can be increased in skeletal muscle.This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit mTOR when applied to isolated cells in culture;[4][38] however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.

Some (e.g. temsirolimus, everolimus) are beginning to be used in the treatment of cancer.[39][40] mTOR inhibitors may also be useful for treating several age-associated diseases.[41] Ridaforolimus is another mTOR inhibitor, currently in clinical development.

Interactions

Mammalian target of rapamycin has been shown to interact with:[42]

References

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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. doi:10.4161/cc.5.21.3408. 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