Target of rapamycin (TOR): Balancing the opposing forces of protein synthesis and degradation

Current Opinion in Genetics and Development

Volumn 9, Issue 1, 1999, Pages 49-54

  Dennis, Patrick B ^a   Fumagalli, Stefano ^a   Thomas, George ^a  

^a FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

MACROLIDE; RAPAMYCIN;

CELL GROWTH; CELL PROLIFERATION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; MITOGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION;

BACTERIA (MICROORGANISMS);

EID: 0032999830     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(99)80007-0     Document Type: Article

References (53)

1. Heitman J, Movva NR, Hall MN Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 253:1991;905-909.
2. 1 progression. Cell. 73:1993;585-596.
3. 1 progression in yeast. Mol Biol Cell. 7:1996;25-42.
4. Schmidt A, Kunz J, Hall MN TOR2 is required for organization of the actin cytoskeleton in yeast. Proc Natl Acad Sci USA. 93:1996;13780-13785.
5. Zheng X-F, Florentino D, Chen J, Crabtree GR, Schreiber SL TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell. 82:1995;121-130.
6. Snyder SH, Lai MM, Burnett PE Immunophilins in the nervous system. Neuron. 21:1998;283-294.
7. Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature. 377:1995;441-446.
8. Chen J, Zheng X-F, Brown Ej, Schreiber SL Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA. 92:1995;4947-4951.
9. Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr., Abraham RT Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 277:1997;99-101.
10. s6k at T389 despite lack of homology between this site and those in 4E-BP1.
11. Andrade MA, Bork P HEAT repeats in the Huntington's disease protein. Nat Genet. 11:1995;115-116.
12. Scott PH, Brunn GJ, Kohn AD, Roth RR, Lawrence JC Jr. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA. 95:1998;7772-7777. Activation of mTOR by insulin is concomitant with its phosphorylation. Treatment of active mTOR with PP1 reduces its activity to basal levels suggesting that mTOR activation requires phosphorylation. Induction of a membrane-targeted form of PKB leads to mTOR phosphorylation and activation, arguing that PKB is a component of the pathway which signals to mTORs.
13. Gingras A-C, Kennedy SG, O'Leary MA, Sonenberg N, Hay N 4E-BP1, a repressor of mRNA translation, is phosphorylated and activated by the Akt (PKB) signaling pathway. Genes Dev. 12:1998;502-513. The authors provide evidence that 4E-BP1 phosphorylation is controlled by the PKB signaling pathway. Expression of membrane-targeted PKB leads to 4E-BP1 phosphorylation and dissociation from eIF-4E in a rapamycin-sensitive and wortmannin-insensitive manner. Conversely expression of kinase-dead PKB reduces insulin-induced phosphorylation of 4E-BP1.
14. Thomas G, Hall MN Tor signalling and control of cell growth. Curr Biol. 9:1997;782-787.
15. s6k. Mol Cell Biol. 17:1997;5426-5436.
16. Sonenberg N, Gingras A-C The mRNA 5′ cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol. 10:1998;268-275.
17. Graves LM, Bornfeld KE, Argast GM, Krebs EG, Kong X, Lin TA, Lawrence JC Jr. cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci USA. 92:1995;7222-7226.
18. Beretta L, Gingras A-C, Svitkin YV, Hall MN, Sonenberg N Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15:1996;658-664.
19. s6k pathway and is independent of mitogen-activated protein kinase. Proc Natl Acad Sci USA. 93:1996;4076-4080.
20. s6k activation from rapamycin, an effect dependent on mTOR kinase activity.
21. Fadden P, Haystead TAJ, Lawrence JC Jr. Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J Biol Chem. 272:1997;10240-10247. This report describes the identification of five S/TP phosphorylation sites including T36, T45, S64, T69 and S82 of 4E-BP1 which are phosphorylated in vitro by immunoprecipitated mTOR. Phosphorylation of the same sites in insulin-treated adipocytes is abolished by rapamycin.
22. Brunn GJ, Fadden P, Haystead T, Lawrence JC Jr. The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J Biol Chem. 272:1997;32547-32550.
23. s6k. EMBO J. 12:1997;3693-3704.
24. s6k defines its role in protein synthesis and rapamycin sensitivity. Proc Natl Acad Sci USA. 95:1998;5033-5038.
25. s6k, S6K2.
26. s6k. FEBS Lett. 410:1997;78-82.
27. 389 are differentially regulated by rapamycin-insensitive kinase-kinases. Mol Cell Biol. 16:1996;6242-6251.
28. Begum N, Ragolia L cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells. J Biol Chem. 271:1996;31166-31171.
29. oprogram of transcriptional repression in yeast by interfering with the TOR signaling pathway. Mol Cell Biol. 18:1998;4463-4470. Rapamycin strongly inhibits Pol I and Pol III transcription in S. cerevisiae. Pol III inhibition is most likely mediated directly through inhibition of TOR rather than a secondary effect caused by translation inhibition. In vitro experiments suggest that the inhibition is exerted through TFIIIB.
30. van Zyl W, Huang W, Sneddon AA, Stark M, Camier S, Werner M, Marck C, Sentenac A, Broach JR Inactivation of the protein phosphatase 2A regulatory subunit A results in morphological and transcriptional defects in Saccharomyces cerevisiae. Mol Cell Biol. 12:1992;4946-4959.
31. Mahajan PB Modulation of transcription of rRNA genes by rapamycin. Int J Immunopharmacol. 16:1994;711-721.
32. Leicht M, Simm A, Bertsch G, Hoppe J Okadaic acid induces cellular hypertrophy in AKR-2B fibroblasts: involvement of the p70S6 kinase in the onset of protein and rRNA synthesis. Cell Growth Differ. 7:1996;1199-1209.
33. White RJ Regulation of RNA polymerases I and III by the retinoblastoma protein: a mechanism for growth control? Trends Biochem Sci. 22:1997;77-80.
34. Taya Y RB kinases and RB-binding proteins: new points of view. Trends Biochem Sci. 22:1997;14-17.
35. Akimoto K, Nakaya M, Yamanaka T, Tanaka J, Matsuda S, Weng Q-P, Avruch J, Ohno S Atypical protein kinase C lambda binds and regulates p70 S6 kinase. Biochem J. 335:1998;417-424.
36. kip1 with cdk2 leading to inhibition of S-phase entry.
37. Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. 273:1998;29864-29872.
38. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massagué J, Crabtree GR, Roberts JM Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature. 372:1994;570-573.
39. Berset C, Trachsel H, Altmann M The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 95:1998;4264-4269.
40. Schmidt A, Beck T, Koller A, Kunz J, Hall MN The TOR nutrient- signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J. 17:1998;6924-6931. Suggests a central role for the TOR pathway as a sensor of nutrient availability. When cells are grown on a poor source of nitrogen, or in the presence of rapamycin, the tryptophan permease, TAT2, is degraded. This effect is abolished in the TOR2-1 rapamycin resistant mutant and overexpression of the putative kinase NPR1 counteracts the effect of TOR2-1 and promotes TAT2 degradation. The TOR pathway phosphorylates and inactivates NPR1; rapamycin-induced dephosphorylation and activation of NPR1 is prevented in a rapamycin-resistant TAP42 mutant, suggesting that TAP42 is an effector of the TOR pathway in the control of TAT2 turnover.
41. Di Como CJ, Arndt KT Nutrients, via the Tor proteins, stimulate the association of Tap42 with Type 2A phophatases. Genes Dev. 10:1996;1904-1916.
42. Murata K, Wu J, Brautigan DL B cell receptor-associated protein α4 displays rapamycin-sensitive binding to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci USA. 94:1997;10624-10629.
43. Inui S, Sanjo H, Maeda K, Yamamoto H, Miyamoto E, Sakaguchi N Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A. Blood. 92:1998;539-546.
44. Chen J, Peterson RT, Schreiber SL α4 associates with protein phosphatase 2A, 4 and 6. Biochem Biophys Res Commun. 247:1998;827-832.
45. Nanahoshi M, Nishiuma T, Tsujishita Y, Hara K, Inui S, Sakaguchi N, Yonezawa K Regulation of protein phosphatase 2A catalytic activity by α4 and its yeast homolog Tap42. Biochem Biophys Res Commun. 251:1998;520-526.
46. Dunn WA Jr. Autophagy and related mechanisms of lysosome-mediated protein degradation. Trends Cell Biol. 4:1994;139-143.
47. Noda T, Ohsumi Y Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 273:1998;3963-3966. Rapamycin induces autophagy in cells grown in a nutrient-rich medium. A similar phenomenon is observed in a yeast strain bearing a tor2 temperature-sensitive allele when cells are grown at the non-permissive temperature suggesting that autophagy is under control of TOR.
48. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y A protein conjugation system essential for autophagy. Nature. 395:1998;395-398. The authors describe a pathway for autophagy in yeast involving the products of 14 previously identified genes. The process is reminiscent of the ubiquitin pathway in that it involves ATP-dependent conjugation of Apg12 to a target protein, Apg5. The process requires the function of the Apg7 protein, which shares significant homology with the E1-activating enzyme of the ubiquitin system. Apg12 and Apg5 have mammalian homologues suggesting conservation of the system throughout evolution.
49. Hammond EM, Brunet CL, Johnson GD, Parkhill J, Milner AE, Brady G, Gregory CD, Grand RJA Homology between a human apoptosis specific protein and the product of APG5, a gene involved in autophagy in yeast. FEBS Lett. 425:1998;391-395.
50. Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 270:1995;2320-2326.
51. s6k mutant is not affected by absence of amino acids suggesting that mTOR acts as a monitor which, according to nutrient availability, modulates the activity of protein synthesis regulators.
52. Wang X, Campbell LE, Miller CM, Proud CG Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem J. 334:1998;261-267.
53. Altman M, Schmitz N, Berset C, Trachsel H A novel inhibitor of cap-dependent translation initiation in yeast: p20 competes with eIF4G for binding to eIF4E. EMBO J. 16:1997;1114-1121.