MTOR and cancer: Many loops in one pathway

Current Opinion in Cell Biology

Volumn 22, Issue 2, 2010, Pages 169-176

  Efeyan, Alejo ^a,b   Sabatini, David M ^a,b  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING PROTEIN; INSULIN RECEPTOR SUBSTRATE 1; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MESSENGER RNA; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE B; PROTEIN MDM2; PROTEIN P53; PROTEIN S6K1; TRANSCRIPTION FACTOR FOXO; TUBERIN; UNCLASSIFIED DRUG;

BINDING AFFINITY; CELL CYCLE PROGRESSION; CELL DIVISION; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; CYTOPLASM; ENZYME SPECIFICITY; GENE ACTIVATION; GENE EXPRESSION PROFILING; GENE FUNCTION; HUMAN; MALIGNANT NEOPLASTIC DISEASE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION; TRANSLATION INITIATION;

ANIMALS; FEEDBACK, PHYSIOLOGICAL; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION;

MAMMALIA;

EID: 77951231349     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ceb.2009.10.007     Document Type: Review

References (58)

1. Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S., Tokunaga C., Avruch J., Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002, 110:177-189.
2. Kim D.H., Sarbassov D.D., Ali S.M., King J.E., Latek R.R., Erdjument-Bromage H., Tempst P., Sabatini D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110:163-175.
3. Kim D.H., Sarbassov D.D., Ali S.M., Latek R.R., Guntur K.V., Erdjument-Bromage H., Tempst P., Sabatini D.M. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003, 11:895-904.
4. Loewith R., Jacinto E., Wullschleger S., Lorberg A., Crespo J.L., Bonenfant D., Oppliger W., Jenoe P., Hall M.N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002, 10:457-468.
5. Peterson T.R., Laplante M., Thoreen C.C., Sancak Y., Kang S.A., Kuehl W.M., Gray N.S., Sabatini D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009, 137:873-886.
6. Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A., Spooner E., Carr S.A., Sabatini D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007, 25:903-915.
7. Vander Haar E., Lee S.I., Bandhakavi S., Griffin T.J., Kim D.H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007, 9:316-323.
8. Frias M.A., Thoreen C.C., Jaffe J.D., Schroder W., Sculley T., Carr S.A., Sabatini D.M. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006, 16:1865-1870.
9. Jacinto E., Facchinetti V., Liu D., Soto N., Wei S., Jung S.Y., Huang Q., Qin J., Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006, 127:125-137.
10. Jacinto E., Loewith R., Schmidt A., Lin S., Ruegg M.A., Hall A., Hall M.N. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004, 6:1122-1128.
11. Sarbassov D.D., Ali S.M., Kim D.H., Guertin D.A., Latek R.R., Erdjument-Bromage H., Tempst P., Sabatini D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004, 14:1296-1302.
12. Yang Q., Inoki K., Ikenoue T., Guan K.L. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 2006, 20:2820-2832.
13. Ma X.M., Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009, 10:307-318.
14. Kim E., Goraksha-Hicks P., Li L., Neufeld T.P., Guan K.L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008, 10:935-945.
15. Sancak Y., Peterson T.R., Shaul Y.D., Lindquist R.A., Thoreen C.C., Bar-Peled L., Sabatini D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 320:1496-1501.
16. Harrington L.S., Findlay G.M., Gray A., Tolkacheva T., Wigfield S., Rebholz H., Barnett J., Leslie N.R., Cheng S., Shepherd P.R., et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004, 166:213-223.
17. Hartley D., Cooper G.M. Role of mTOR in the degradation of IRS-1: regulation of PP2A activity. J Cell Biochem 2002, 85:304-314.
18. Haruta T., Uno T., Kawahara J., Takano A., Egawa K., Sharma P.M., Olefsky J.M., Kobayashi M. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 2000, 14:783-794.
19. Takano A., Usui I., Haruta T., Kawahara J., Uno T., Iwata M., Kobayashi M. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol Cell Biol 2001, 21:5050-5062.
20. Um S.H., Frigerio F., Watanabe M., Picard F., Joaquin M., Sticker M., Fumagalli S., Allegrini P.R., Kozma S.C., Auwerx J., et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004, 431:200-205.
21. Zhang H., Bajraszewski N., Wu E., Wang H., Moseman A.P., Dabora S.L., Griffin J.D., Kwiatkowski D.J. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 2007, 117:730-738.
22. Carracedo A., Ma L., Teruya-Feldstein J., Rojo F., Salmena L., Alimonti A., Egia A., Sasaki A.T., Thomas G., Kozma S.C., et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008, 118:3065-3074.
23. Feng Z., Hu W., de Stanchina E., Teresky A.K., Jin S., Lowe S., Levine A.J. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 2007, 67:3043-3053.
24. Jones R.G., Plas D.R., Kubek S., Buzzai M., Mu J., Xu Y., Birnbaum M.J., Thompson C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005, 18:283-293.
25. Budanov A.V., Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008, 134:451-460.
26. Freeman D.J., Li A.G., Wei G., Li H.H., Kertesz N., Lesche R., Whale A.D., Martinez-Diaz H., Rozengurt N., Cardiff R.D., et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 2003, 3:117-130.
27. Manning B.D., Cantley L.C. AKT/PKB signaling: navigating downstream. Cell 2007, 129:1261-1274.
28. Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 307:1098-1101.
29. Huang J., Dibble C.C., Matsuzaki M., Manning B.D. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008, 28:4104-4115.
30. Dibble C.C., Asara J.M., Manning B.D. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 2009, 29:5657-5670.
31. Choo A.Y., Yoon S.O., Kim S.G., Roux P.P., Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A 2008, 105:17414-17419.
32. Feldman M.E., Apsel B., Uotila A., Loewith R., Knight Z.A., Ruggero D., Shokat K.M. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009, 7:e38.
33. Garcia-Martinez J.M., Moran J., Clarke R.G., Gray A., Cosulich S.C., Chresta C.M., Alessi D.R. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 2009, 421:29-42.
34. Thoreen C.C., Kang S.A., Chang J.W., Liu Q., Zhang J., Gao Y., Reichling L.J., Sim T., Sabatini D.M., Gray N.S. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009, 284:8023-8032.
35. Yu K., Toral-Barza L., Shi C., Zhang W.G., Lucas J., Shor B., Kim J., Verheijen J., Curran K., Malwitz D.J., et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009, 69:6232-6240.
36. O'Reilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., Lane H., Hofmann F., Hicklin D.J., Ludwig D.L., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66:1500-1508.
37. Ma L., Teruya-Feldstein J., Behrendt N., Chen Z., Noda T., Hino O., Cordon-Cardo C., Pandolfi P.P. Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev 2005, 19:1779-1786.
38. Manning B.D., Logsdon M.N., Lipovsky A.I., Abbott D., Kwiatkowski D.J., Cantley L.C. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005, 19:1773-1778.
39. Skeen J.E., Bhaskar P.T., Chen C.C., Chen W.S., Peng X.D., Nogueira V., Hahn-Windgassen A., Kiyokawa H., Hay N. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 2006, 10:269-280.
40. Vasudevan K.M., Barbie D.A., Davies M.A., Rabinovsky R., McNear C.J., Kim J.J., Hennessy B.T., Tseng H., Pochanard P., Kim S.Y., et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009, 16:21-32.
41. Garcia-Martinez J.M., Alessi D.R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008, 416:375-385.
42. Sarbassov D.D., Ali S.M., Sengupta S., Sheen J.H., Hsu P.P., Bagley A.F., Markhard A.L., Sabatini D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006, 22:159-168.
43. Shor B., Zhang W.G., Toral-Barza L., Lucas J., Abraham R.T., Gibbons J.J., Yu K. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 2008, 68:2934-2943.
44. Shiota C., Woo J.T., Lindner J., Shelton K.D., Magnuson M.A. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 2006, 11:583-589.
45. Guertin D.A., Stevens D.M., Saitoh M., Kinkel S., Crosby K., Sheen J.H., Mullholland D.J., Magnuson M.A., Wu H., Sabatini D.M. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009, 15:148-159.
46. Nardella C., Carracedo A., Alimonti A., Hobbs R.M., Clohessy J.G., Chen Z., Egia A., Fornari A., Fiorentino M., Loda M., et al. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci Signal 2009, 2:ra2.
47. Guertin D.A., Sabatini D.M. The pharmacology of mTOR inhibition. Sci Signal 2009, 2:pe24.
48. Brachmann S., Fritsch C., Maira S.M., Garcia-Echeverria C. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr Opin Cell Biol 2009, 21:194-198.
49. Engelman J.A., Chen L., Tan X., Crosby K., Guimaraes A.R., Upadhyay R., Maira M., McNamara K., Perera S.A., Song Y., et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008, 14:1351-1356.
50. Ihle N.T., Lemos R., Wipf P., Yacoub A., Mitchell C., Siwak D., Mills G.B., Dent P., Kirkpatrick D.L., Powis G. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 2009, 69:143-150.
51. Torbett N.E., Luna-Moran A., Knight Z.A., Houk A., Moasser M., Weiss W., Shokat K.M., Stokoe D. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 2008, 415:97-110.
52. Inoki K., Li Y., Xu T., Guan K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003, 17:1829-1834.
53. Inoki K., Zhu T., Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115:577-590.
54. Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A., Vasquez D.S., Turk B.E., Shaw R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008, 30:214-226.
55. Hemminki A., Markie D., Tomlinson I., Avizienyte E., Roth S., Loukola A., Bignell G., Warren W., Aminoff M., Hoglund P., et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998, 391:184-187.
56. Crino P.B., Nathanson K.L., Henske E.P. The tuberous sclerosis complex. N Engl J Med 2006, 355:1345-1356.
57. Manning B.D., Tee A.R., Logsdon M.N., Blenis J., Cantley L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002, 10:151-162.
58. Orloff M.S., Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene 2008, 27:5387-5397.