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Gene Review

Tor  -  Target of rapamycin

Drosophila melanogaster

Synonyms: 5092, CG5092, CT16317, CT24745, CT24817, ...
 
 
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Disease relevance of Tor

  • Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity [corrected] [1].
  • These data imply that pathological situations that increase TOR activity might perturb the ability of the whole organism to cope with stress causing disease progression and aging [2].
  • The well-conserved Rheb-Target-of-rapamycin (TOR)-S6-kinase (S6K) signaling pathway regulates several cellular processes and has been shown to influence lifespan and diseases such as cancer and neurodegenerative disorders [2].
  • Detailed analyses of the rl mutations demonstrated moderate dominant activities of these alleles in the Torso (Tor) signaling pathway, which explains the weak dominant female sterility observed in this study [3].
  • Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease [4].
 

Psychiatry related information on Tor

 

High impact information on Tor

  • Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains [4].
  • This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects [4].
  • This involves TSC/TOR signaling in the fat body, and a remote inhibition of organismal growth via local repression of PI3-kinase signaling in peripheral tissues [5].
  • In this issue of Cell, Colombani et al. demonstrate that amino acid-responsive TOR signaling in the Drosophila fat body modulates insulin signaling and growth in peripheral tissues [6].
  • Identification of TOR signaling complexes: more TORC for the cell growth engine [7].
 

Biological context of Tor

  • Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller [8].
  • We used RNA interference (RNAi) to target components of the PI3K, Akt, and TOR pathways [9].
  • Thus, in cells lacking TOR, autophagy plays a protective role that is dominant over its potential role as a growth suppressor [10].
  • Instead, inhibition of autophagy enhances TOR mutant phenotypes, including reduced cell size, growth rate, and survival [10].
  • As in mammalian cells, the kinase activity of dTOR is required for growth factor-dependent phosphorylation of p70 S6 kinase (p70(S6K)) in vitro, and we demonstrate that overexpression of p70(S6K) in vivo can rescue dTOR mutant animals to viability [11].
 

Anatomical context of Tor

  • Here, we show that signaling through TOR and its upstream regulators PI3K and Rheb is necessary and sufficient to suppress starvation-induced autophagy in the Drosophila fat body [10].
  • Recent findings, however, indicate that TOR also controls the growth of non-proliferating cells, such as neurons and muscle cells [12].
  • Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton [13].
  • In a heterologous Xenopus oocyte system, PATH also activates the TOR target S6 kinase in an amino acid-dependent way [14].
  • mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells [15].
 

Associations of Tor with chemical compounds

  • 4E-BP activity is controlled by TOR (Target of Rapamycin) [16].
  • Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels [17].
  • Here, we identify four tyrosine residues (Y644, Y698, Y767, and Y772) that become phosphorylated after activation of the Torso (Tor) receptor tyrosine kinase [18].
  • To investigate the function of each P-Y residue in Tor signaling, we have generated transgenic Drosophila embryos expressing mutant Tor receptors containing either single or multiple tyrosine to phenylalanine substitutions [18].
  • More striking, despite dPKB-dPI(3)K-independence, dS6K activity is dependent on the Drosophila homologue of the phosphoinositide-dependent protein kinase 1, dPDK1, demonstrating that both dPDK1, as well as dTOR, mediated dS6K activation is phosphatidylinositide-3,4,5-trisphosphate (PIP3)-independent [19].
 

Physical interactions of Tor

  • Insulin delays the progression of Drosophila cells through G2/M by activating the dTOR/dRaptor complex [20].
 

Regulatory relationships of Tor

  • Rheb promotes cell growth as a component of the insulin/TOR signalling network [1].
  • The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima [21].
  • We present genetic evidence that TOR signaling stimulates bulk endocytic uptake and inhibits the targeted endocytic degradation of the amino acid importer Slimfast [22].
 

Other interactions of Tor

  • Target of Rapamycin (TOR) mediates a signalling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth [23].
  • In addition, Tap42 is not required for increased cell growth in response to activation of TOR signaling [24].
  • In a genetic screen for novel TOR interactors in Drosophila melanogaster, we have identified the clathrin-uncoating ATPase Hsc70-4, which is a key regulator of endocytosis [22].
  • These transporters genetically interact with TOR and other InR signalling components, indicating that they control growth by directly or indirectly modulating the effects of TOR signalling [14].

References

  1. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Saucedo, L.J., Gao, X., Chiarelli, D.A., Li, L., Pan, D., Edgar, B.A. Nat. Cell Biol. (2003) [Pubmed]
  2. Increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress. Patel, P.H., Tamanoi, F. J. Cell. Sci. (2006) [Pubmed]
  3. Genetic analysis of rolled, which encodes a Drosophila mitogen-activated protein kinase. Lim, Y.M., Nishizawa, K., Nishi, Y., Tsuda, L., Inoue, Y.H., Nishida, Y. Genetics (1999) [Pubmed]
  4. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J., Rubinsztein, D.C. Nat. Genet. (2004) [Pubmed]
  5. A nutrient sensor mechanism controls Drosophila growth. Colombani, J., Raisin, S., Pantalacci, S., Radimerski, T., Montagne, J., Léopold, P. Cell (2003) [Pubmed]
  6. Amino acids and the humoral regulation of growth: fat bodies use slimfast. Bradley, G.L., Leevers, S.J. Cell (2003) [Pubmed]
  7. Identification of TOR signaling complexes: more TORC for the cell growth engine. Abraham, R.T. Cell (2002) [Pubmed]
  8. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Yang, Q., Inoki, K., Ikenoue, T., Guan, K.L. Genes Dev. (2006) [Pubmed]
  9. Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila melanogaster. Miron, M., Lasko, P., Sonenberg, N. Mol. Cell. Biol. (2003) [Pubmed]
  10. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Scott, R.C., Schuldiner, O., Neufeld, T.P. Dev. Cell (2004) [Pubmed]
  11. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Zhang, H., Stallock, J.P., Ng, J.C., Reinhard, C., Neufeld, T.P. Genes Dev. (2000) [Pubmed]
  12. Tor signalling in bugs, brain and brawn. Jacinto, E., Hall, M.N. Nat. Rev. Mol. Cell Biol. (2003) [Pubmed]
  13. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Sarbassov, D.D., Ali, S.M., Kim, D.H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M. Curr. Biol. (2004) [Pubmed]
  14. PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Goberdhan, D.C., Meredith, D., Boyd, C.A., Wilson, C. Development (2005) [Pubmed]
  15. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Murakami, M., Ichisaka, T., Maeda, M., Oshiro, N., Hara, K., Edenhofer, F., Kiyama, H., Yonezawa, K., Yamanaka, S. Mol. Cell. Biol. (2004) [Pubmed]
  16. 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Teleman, A.A., Chen, Y.W., Cohen, S.M. Genes Dev. (2005) [Pubmed]
  17. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Luong, N., Davies, C.R., Wessells, R.J., Graham, S.M., King, M.T., Veech, R., Bodmer, R., Oldham, S.M. Cell metabolism. (2006) [Pubmed]
  18. Synergistic activities of multiple phosphotyrosine residues mediate full signaling from the Drosophila Torso receptor tyrosine kinase. Gayko, U., Cleghon, V., Copeland, T., Morrison, D.K., Perrimon, N. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  19. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Radimerski, T., Montagne, J., Rintelen, F., Stocker, H., van der Kaay, J., Downes, C.P., Hafen, E., Thomas, G. Nat. Cell Biol. (2002) [Pubmed]
  20. Insulin delays the progression of Drosophila cells through G2/M by activating the dTOR/dRaptor complex. Wu, M.Y., Cully, M., Andersen, D., Leevers, S.J. EMBO J. (2007) [Pubmed]
  21. The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima. Dekanty, A., Lavista-Llanos, S., Irisarri, M., Oldham, S., Wappner, P. J. Cell. Sci. (2005) [Pubmed]
  22. TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth. Hennig, K.M., Colombani, J., Neufeld, T.P. J. Cell Biol. (2006) [Pubmed]
  23. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R.S., Ru, B., Pan, D. Nat. Cell Biol. (2002) [Pubmed]
  24. The phosphatase subunit tap42 functions independently of target of rapamycin to regulate cell division and survival in Drosophila. Cygnar, K.D., Gao, X., Pan, D., Neufeld, T.P. Genetics (2005) [Pubmed]
 
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