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From Wikipedia, the free encyclopedia

FK506 binding protein 12-rapamycin associated protein 1

PDB rendering based on 1aue.
Available structures
1aue, 1fap, 1nsg, 2fap, 2gaq, 3fap, 4fap
Symbols FRAP1; FLJ44809; FRAP; FRAP2; MTOR; RAFT1; RAPT1
External IDs OMIM601231 MGI1928394 HomoloGene3637 GeneCards: FRAP1 Gene
RNA expression pattern
PBB GE FRAP1 202288 at tn.png
More reference expression data
Species Human Mouse
Entrez 2475 56717
Ensembl ENSG00000198793 ENSMUSG00000028991
UniProt P42345 Q3T9E1
RefSeq (mRNA) NM_004958 XM_622902
RefSeq (protein) NP_004949 XP_622902
Location (UCSC) Chr 1:
11.09 - 11.25 Mb
Chr 4:
147.29 - 147.4 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 integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and mitogens.[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 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, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin.[4][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]


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 effecting pre-existing mTORC2s, can bind to free mTOR molecules, thus inhibiting the formation of new mTORC2.[26]


mTOR signaling pathway.[1]

Decreased TOR activity has been found to slow aging in S. cerevisiae, C. elegans, and D. melanogaster.[27][28][29] 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.[30]

It's hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTor activity.[27]

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.[31]

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


Mammalian target of rapamycin has been shown to interact with UBQLN1,[32] CLIP1,[33] STAT1,[34] FKBP1A,[35][36][37][38][39][40] STAT3,[41][42] AKT1,[43][44][45] GPHN,[46] KIAA1303,[35][36][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] Abl gene,[65] RICTOR,[35][36][51][53][61][63][64] EIF4EBP1,[47][48][50][59][66][67][68][69] PRKCD,[70] P70-S6 Kinase 1,[48][59][66][58][67][63][71][68][72][73][74][75][76][77][78] EIF3F[79] and RHEB.[66][80][81][82]


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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. 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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