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Mtor  -  mechanistic target of rapamycin...

Rattus norvegicus

Synonyms: FK506-binding protein 12-rapamycin complex-associated protein 1, FKBP12-rapamycin complex-associated protein, Frap1, Mammalian target of rapamycin, Mechanistic target of rapamycin, ...
 
 
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Disease relevance of Frap1

  • The tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) cascade integrates growth factor and nutritional signals to regulate the synthesis of specific proteins [1].
  • However, it is still unclear whether activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance [2].
  • The purpose of this study was to identify the potential downstream functions associated with mammalian target of rapamycin (mTOR) signaling during myotube hypertrophy [3].
  • We propose that calcium-induced activation of cPKC-alpha hypoxia partially protects an activity of mTOR from hypoxic inhibition [4].
  • The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy [5].
 

High impact information on Frap1

  • We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner [6].
  • These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells [7].
  • We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals [8].
  • Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo [5].
  • Furthermore, rapamycin, a selective blocker of mTOR, blocked hypertrophy in all models tested, without causing atrophy in control muscles [5].
 

Chemical compound and disease context of Frap1

  • In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity [2].
  • This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity [9].
  • Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight [10].
 

Biological context of Frap1

  • Together, these findings highlight a novel role of the TSC2/mTOR pathway in regulating microtubule-dependent protein transport [11].
  • Recent studies have identified TSC1 and TSC2, two tumor suppressor genes involved in tuberous sclerosis complex, as regulators of the mammalian target of rapamycin (mTOR) pathway [11].
  • Phosphorylation of p70(S6K), a known target of mTOR, occurred rapidly following T3 treatment and was inhibited by rapamycin and wortmannin [12].
  • In addition, we demonstrated that inhibition of the mTOR pathway with rapamycin can prevent insulin resistance caused by chronic hyperinsulinaemia in liver and muscle [13].
  • The mammalian target of rapamycin (mTOR) promotes increased protein synthesis required for cell growth [14].
 

Anatomical context of Frap1

  • AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling [15].
  • No increases in IRS-1/2 serine phosphorylation and mTOR activity were observed in white adipose tissue [13].
  • We used Rat-1 fibroblasts expressing the alpha(1A) adrenergic receptor to study if this G(q)-coupled receptor uses PLD to regulate mTOR signaling [14].
  • Taken together, these data indicate that mTOR-dependent translation activation is essential for the upregulation of local protein synthesis in neuronal dendrites [16].
  • To test our hypothesis, we directly administered rapamycin (an inhibitor of mTOR), glucose, 5-aminoimidazole-4-carboxamide-1beta-4-ribonucleoside (AICAR; an activator of AMP kinase), or glucose plus rapamycin into the dorsal hippocampus after we trained rats in the Morris water maze task [1].
 

Associations of Frap1 with chemical compounds

 

Physical interactions of Frap1

  • Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway [18].
  • Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase [19].
 

Enzymatic interactions of Frap1

  • The mammalian target of rapamycin (mTOR) has been proposed to directly phosphorylate 4E-BP1 [20].
  • We have investigated the effects of insulin, amino acids, and the degree of muscle loading on the phosphorylation of Ser(2448), a site in the mammalian target of rapamycin (mTOR) phosphorylated by protein kinase B (PKB) in vitro [21].
 

Regulatory relationships of Frap1

  • Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1 [22].
  • This study demonstrates that mTOR is a component of a cytokine-triggered protein kinase cascade leading to the phosphorylation of the eukaryotic initiation factor-4E (eIF-4E) binding protein, PHAS-1, in activated T lymphocytes [23].
 

Other interactions of Frap1

  • Here, we show that modulation of mTOR activity affects caveolin-1 localization and that this effect is independent of p70S6K [11].
  • Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid [24].
  • 40 S ribosomal protein S6, a target of p70(S6K), and 4E-BP1, a target of mTOR, were both phosphorylated within 15-25 min of T3 treatment and could be inhibited by wortmannin and rapamycin [12].
  • Treatment of cells with rapamycin, an inhibitor of the mammalian target of mTOR, resulted in a 47% and a 53% decrease in the AP activity induced by OP-1 alone and by OP-1 plus IGF-I, respectively [25].
  • T3 treatment rapidly increased PI3K activity by 52 +/- 3% (p < 0.005), which resulted in increased phosphorylation of downstream kinases Akt and mammalian target of rapamycin (mTOR) [12].
 

Analytical, diagnostic and therapeutic context of Frap1

References

  1. Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-Mammalian target of rapamycin pathway. Dash, P.K., Orsi, S.A., Moore, A.N. J. Neurosci. (2006) [Pubmed]
  2. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Khamzina, L., Veilleux, A., Bergeron, S., Marette, A. Endocrinology (2005) [Pubmed]
  3. mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators. Nader, G.A., McLoughlin, T.J., Esser, K.A. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  4. Calcium signaling stimulates translation of HIF-alpha during hypoxia. Hui, A.S., Bauer, A.L., Striet, J.B., Schnell, P.O., Czyzyk-Krzeska, M.F. FASEB J. (2006) [Pubmed]
  5. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Bodine, S.C., Stitt, T.N., Gonzalez, M., Kline, W.O., Stover, G.L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J.C., Glass, D.J., Yancopoulos, G.D. Nat. Cell Biol. (2001) [Pubmed]
  6. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., Snyder, S.H. Cell (1994) [Pubmed]
  7. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Brunn, G.J., Hudson, C.C., Sekulić, A., Williams, J.M., Hosoi, H., Houghton, P.J., Lawrence, J.C., Abraham, R.T. Science (1997) [Pubmed]
  8. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Fingar, D.C., Salama, S., Tsou, C., Harlow, E., Blenis, J. Genes Dev. (2002) [Pubmed]
  9. Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function. Li, S.Y., Fang, C.X., Aberle, N.S., Ren, B.H., Ceylan-Isik, A.F., Ren, J. J. Endocrinol. (2005) [Pubmed]
  10. Hypothalamic mTOR signaling regulates food intake. Cota, D., Proulx, K., Smith, K.A., Kozma, S.C., Thomas, G., Woods, S.C., Seeley, R.J. Science (2006) [Pubmed]
  11. Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Jiang, X., Yeung, R.S. Cancer Res. (2006) [Pubmed]
  12. Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. Kenessey, A., Ojamaa, K. J. Biol. Chem. (2006) [Pubmed]
  13. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Ueno, M., Carvalheira, J.B., Tambascia, R.C., Bezerra, R.M., Amaral, M.E., Carneiro, E.M., Folli, F., Franchini, K.G., Saad, M.J. Diabetologia (2005) [Pubmed]
  14. Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling. Ballou, L.M., Jiang, Y.P., Du, G., Frohman, M.A., Lin, R.Z. FEBS Lett. (2003) [Pubmed]
  15. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. Bolster, D.R., Crozier, S.J., Kimball, S.R., Jefferson, L.S. J. Biol. Chem. (2002) [Pubmed]
  16. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., Nawa, H. J. Neurosci. (2004) [Pubmed]
  17. Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside. Reiter, A.K., Bolster, D.R., Crozier, S.J., Kimball, S.R., Jefferson, L.S. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  18. IGF-I activates the eIF4F system in cardiac muscle in vivo. Vary, T.C., Lang, C.H. Mol. Cell. Biochem. (2005) [Pubmed]
  19. Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. Heesom, K.J., Denton, R.M. FEBS Lett. (1999) [Pubmed]
  20. Rapamycin-insensitive regulation of 4e-BP1 in regenerating rat liver. Jiang, Y.P., Ballou, L.M., Lin, R.Z. J. Biol. Chem. (2001) [Pubmed]
  21. Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. Reynolds, T.H., Bodine, S.C., Lawrence, J.C. J. Biol. Chem. (2002) [Pubmed]
  22. Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. Lee, C.C., Huang, C.C., Wu, M.Y., Hsu, K.S. J. Biol. Chem. (2005) [Pubmed]
  23. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. Brunn, G.J., Williams, J., Sabers, C., Wiederrecht, G., Lawrence, J.C., Abraham, R.T. EMBO J. (1996) [Pubmed]
  24. Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid. Kam, Y., Exton, J.H. FASEB J. (2004) [Pubmed]
  25. Inhibition of phosphatidylinositol 3-kinase and p70S6 kinase blocks osteogenic protein-1 induction of alkaline phosphatase activity in fetal rat calvaria cells. Shoba, L.N., Lee, J.C. J. Cell. Biochem. (2003) [Pubmed]
  26. Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle. Hong-Brown, L.Q., Pruznak, A.M., Frost, R.A., Vary, T.C., Lang, C.H. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  27. The mTOR signaling pathway mediates control of ribosomal protein mRNA translation in rat liver. Reiter, A.K., Anthony, T.G., Anthony, J.C., Jefferson, L.S., Kimball, S.R. Int. J. Biochem. Cell Biol. (2004) [Pubmed]
  28. Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN. Mourani, P.M., Garl, P.J., Wenzlau, J.M., Carpenter, T.C., Stenmark, K.R., Weiser-Evans, M.C. Circulation (2004) [Pubmed]
  29. Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Razeghi, P., Sharma, S., Ying, J., Li, Y.P., Stepkowski, S., Reid, M.B., Taegtmeyer, H. Circulation (2003) [Pubmed]
 
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