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Gene Review

Mtor  -  mechanistic target of rapamycin...

Mus musculus

Synonyms: 2610315D21Rik, AI327068, FK506-binding protein 12-rapamycin complex-associated protein 1, FKBP-rapamycin-associated protein FRAP, FKBP12-rapamycin complex-associated protein, ...
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Disease relevance of Frap1


Psychiatry related information on Frap1

  • Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease [6].

High impact information on Frap1


Chemical compound and disease context of Frap1


Biological context of Frap1

  • While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known [1].
  • Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia [1].
  • Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene [1].
  • Translational up-regulation is blocked by inactivation of FRAP signaling by rapamycin, resulting in G(1) cell cycle arrest [15].
  • The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process [16].

Anatomical context of Frap1

  • The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors [3].
  • Although the role of FRAP has been extensively studied in vitro, characterization of mammalian FRAP function in vivo has been limited to the immune system and tumor models [15].
  • Using the mTOR inhibitor rapamycin, we show that mTOR is required for the rapid and sustained serum-induced activation of 45S ribosomal gene transcription (rDNA transcription), a major rate-limiting step in ribosome biogenesis and cellular growth [17].
  • Based on our cell-free kinase and small interference RNA results, we conclude that mTOR complexed to RICTOR is the Ser-473 kinase in 3T3-L1 adipocytes [18].
  • Our results show that Delta10mTORrr signals 4E-BP1 and permits rapamycin-treated myoblasts to differentiate, confirming the mTOR dependence of the inhibition of myogenesis by rapamycin [19].

Associations of Frap1 with chemical compounds

  • In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein [16].
  • Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST [20].
  • The FKBP-12-rapamycin associated protein (FRAP, also known as mTOR and RAFT-1) is a member of the phosphoinositide kinase related kinase family [15].
  • Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639 [21].
  • The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase known to control initiation of translation through two downstream pathways: eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic initiation factor 4E and ribosomal p70 S6 kinase (S6K1) [19].
  • The reduction in 4E-BP1 phosphorylation was associated with a reduction in the abundance of Raptor and mTOR proteins, Raptor-associated mTOR, reduced phosphorylation of the downstream protein p70S6 kinase, and attenuated incorporation of [(14)C]phenylalanine into protein [22].
  • Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone [23].

Physical interactions of Frap1

  • Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801 [1].
  • The effects of insulin on the mammalian target of rapamycin, mTOR, were investigated in 3T3-L1 adipocytes. mTOR protein kinase activity was measured in immune complex assays with recombinant PHAS-I as substrate [24].

Enzymatic interactions of Frap1


Regulatory relationships of Frap1


Other interactions of Frap1


Analytical, diagnostic and therapeutic context of Frap1


  1. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Brugarolas, J., Lei, K., Hurley, R.L., Manning, B.D., Reiling, J.H., Hafen, E., Witters, L.A., Ellisen, L.W., Kaelin, W.G. Genes Dev. (2004) [Pubmed]
  2. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. Le Bacquer, O., Petroulakis, E., Paglialunga, S., Poulin, F., Richard, D., Cianflone, K., Sonenberg, N. J. Clin. Invest. (2007) [Pubmed]
  3. Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene. Bliskovsky, V., Ramsay, E.S., Scott, J., DuBois, W., Shi, W., Zhang, S., Qian, X., Lowy, D.R., Mock, B.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Negative regulation of melanogenesis by phospholipase D1 through mTOR/p70 S6 kinase 1 signaling in mouse B16 melanoma cells. Ohguchi, K., Banno, Y., Nakagawa, Y., Akao, Y., Nozawa, Y. J. Cell. Physiol. (2005) [Pubmed]
  5. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Shi, Y., Yan, H., Frost, P., Gera, J., Lichtenstein, A. Mol. Cancer Ther. (2005) [Pubmed]
  6. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. Lafay-Chebassier, C., Paccalin, M., Page, G., Barc-Pain, S., Perault-Pochat, M.C., Gil, R., Pradier, L., Hugon, J. J. Neurochem. (2005) [Pubmed]
  7. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Aoki, K., Tamai, Y., Horiike, S., Oshima, M., Taketo, M.M. Nat. Genet. (2003) [Pubmed]
  8. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Thomas, G.V., Tran, C., Mellinghoff, I.K., Welsbie, D.S., Chan, E., Fueger, B., Czernin, J., Sawyers, C.L. Nat. Med. (2006) [Pubmed]
  9. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Majumder, P.K., Febbo, P.G., Bikoff, R., Berger, R., Xue, Q., McMahon, L.M., Manola, J., Brugarolas, J., McDonnell, T.J., Golub, T.R., Loda, M., Lane, H.A., Sellers, W.R. Nat. Med. (2004) [Pubmed]
  10. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Yan, H., Frost, P., Shi, Y., Hoang, B., Sharma, S., Fisher, M., Gera, J., Lichtenstein, A. Cancer Res. (2006) [Pubmed]
  11. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. deGraffenried, L.A., Friedrichs, W.E., Russell, D.H., Donzis, E.J., Middleton, A.K., Silva, J.M., Roth, R.A., Hidalgo, M. Clin. Cancer Res. (2004) [Pubmed]
  12. Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Nagai, K., Matsubara, T., Mima, A., Sumi, E., Kanamori, H., Iehara, N., Fukatsu, A., Yanagita, M., Nakano, T., Ishimoto, Y., Kita, T., Doi, T., Arai, H. Kidney Int. (2005) [Pubmed]
  13. In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Ito, D., Fujimoto, K., Mori, T., Kami, K., Koizumi, M., Toyoda, E., Kawaguchi, Y., Doi, R. Int. J. Cancer (2006) [Pubmed]
  14. Alpha7beta1-integrin regulates mechanotransduction and prevents skeletal muscle injury. Boppart, M.D., Burkin, D.J., Kaufman, S.J. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  15. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Hentges, K.E., Sirry, B., Gingeras, A.C., Sarbassov, D., Sonenberg, N., Sabatini, D., Peterson, A.S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  16. The coordinate regulation of the p53 and mTOR pathways in cells. Feng, Z., Zhang, H., Levine, A.J., Jin, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Hannan, K.M., Brandenburger, Y., Jenkins, A., Sharkey, K., Cavanaugh, A., Rothblum, L., Moss, T., Poortinga, G., McArthur, G.A., Pearson, R.B., Hannan, R.D. Mol. Cell. Biol. (2003) [Pubmed]
  18. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. Hresko, R.C., Mueckler, M. J. Biol. Chem. (2005) [Pubmed]
  19. Myogenic differentiation is dependent on both the kinase function and the N-terminal sequence of mammalian target of rapamycin. Shu, L., Zhang, X., Houghton, P.J. J. Biol. Chem. (2002) [Pubmed]
  20. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Rossi, F., Ehlers, I., Agosti, V., Socci, N.D., Viale, A., Sommer, G., Yozgat, Y., Manova, K., Antonescu, C.R., Besmer, P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  21. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Tzatsos, A., Kandror, K.V. Mol. Cell. Biol. (2006) [Pubmed]
  22. FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. Southgate, R.J., Neill, B., Prelovsek, O., El-Osta, A., Kamei, Y., Miura, S., Ezaki, O., McLoughlin, T.J., Zhang, W., Unterman, T.G., Febbraio, M.A. J. Biol. Chem. (2007) [Pubmed]
  23. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Cho, D.C., Cohen, M.B., Panka, D.J., Collins, M., Ghebremichael, M., Atkins, M.B., Signoretti, S., Mier, J.W. Clin. Cancer Res. (2010) [Pubmed]
  24. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Scott, P.H., Brunn, G.J., Kohn, A.D., Roth, R.A., Lawrence, J.C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  25. Modulation of the protein kinase activity of mTOR. Lawrence, J.C., Lin, T.A., McMahon, L.P., Choi, K.M. Curr. Top. Microbiol. Immunol. (2004) [Pubmed]
  26. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. Sugatani, T., Hruska, K.A. J. Biol. Chem. (2005) [Pubmed]
  27. Mammalian target of rapamycin promotes vincristine resistance through multiple mechanisms independent of maintained glycolytic rate. Vanderweele, D.J., Rudin, C.M. Mol. Cancer Res. (2005) [Pubmed]
  28. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. Hahn-Windgassen, A., Nogueira, V., Chen, C.C., Skeen, J.E., Sonenberg, N., Hay, N. J. Biol. Chem. (2005) [Pubmed]
  29. Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes. Gual, P., Gonzalez, T., Grémeaux, T., Barres, R., Le Marchand-Brustel, Y., Tanti, J.F. J. Biol. Chem. (2003) [Pubmed]
  30. mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Hu, X., Pandolfi, P.P., Li, Y., Koutcher, J.A., Rosenblum, M., Holland, E.C. Neoplasia (2005) [Pubmed]
  31. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Shillingford, J.M., Murcia, N.S., Larson, C.H., Low, S.H., Hedgepeth, R., Brown, N., Flask, C.A., Novick, A.C., Goldfarb, D.A., Kramer-Zucker, A., Walz, G., Piontek, K.B., Germino, G.G., Weimbs, T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  32. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Ly, C., Arechiga, A.F., Melo, J.V., Walsh, C.M., Ong, S.T. Cancer Res. (2003) [Pubmed]
  33. Met acts on Mdm2 via mTOR to signal cell survival during development. Moumen, A., Patané, S., Porras, A., Dono, R., Maina, F. Development (2007) [Pubmed]
  34. Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Jiang, X., Yeung, R.S. Cancer Res. (2006) [Pubmed]
  35. Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. Lenz, G., Avruch, J. J. Biol. Chem. (2005) [Pubmed]
  36. Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. Williamson, D.L., Kubica, N., Kimball, S.R., Jefferson, L.S. J. Physiol. (Lond.) (2006) [Pubmed]
  37. Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Lee, L., Sudentas, P., Dabora, S.L. Genes Chromosomes Cancer (2006) [Pubmed]
  38. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Mabuchi, S., Altomare, D.A., Connolly, D.C., Klein-Szanto, A., Litwin, S., Hoelzle, M.K., Hensley, H.H., Hamilton, T.C., Testa, J.R. Cancer Res. (2007) [Pubmed]
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