Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling

Current Medicinal Chemistry

Volumn 19, Issue 22, 2012, Pages 3748-3762

  Altomare, D A ^a   Khaled, A R ^a  

^a UNIVERSITY OF CENTRAL FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Growth factor signaling; Metabolism; Molecular targeted inhibition; Signal transduction; Tumor progression

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; AZD 2014; AZD 8055; EVEROLIMUS; INK 128; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PROTEIN KINASE B; RIDAFOROLIMUS; TEMSIROLIMUS; UNCLASSIFIED DRUG;

CALORIC RESTRICTION; CANCER RESEARCH; CD8+ T LYMPHOCYTE; CELL GROWTH; CELL METABOLISM; CELL VIABILITY; ENZYME ACTIVATION; ENZYME ACTIVITY; GROWTH REGULATION; HOMEOSTASIS; HUMAN; IMMUNOCOMPETENT CELL; INSULIN RESPONSE; INTRACELLULAR SIGNALING; KIDNEY CARCINOMA; LONGEVITY; MOLECULARLY TARGETED THERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUCLEAR REPROGRAMMING; PROTEIN FUNCTION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR GROWTH; TUMOR IMMUNITY;

HOMEOSTASIS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; LYMPHOCYTES; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN ISOFORMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84865210598     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712801661130     Document Type: Review

References (107)

1. Bhaskar, P. T.; Hay, N., The two TORCs and Akt. Dev Cell 2007, 12 (4), 487-502. (Pubitemid 46523652)
2. Manning, B. D.; Cantley, L. C., AKT/PKB signaling: navigating downstream. Cell 2007, 129 (7), 1261-1274. (Pubitemid 46962095)
3. Franke, T. F., PI3K/Akt: getting it right matters. Oncogene 2008, 27, 6473-6488.
4. Mahajan, K.; Mahajan, N. P., PI3K-independent AKT activation in cancers: A treasure trove for novel therapeutics. J Cell Physiol 2012, Feb 3. [Epub ahead of print].
5. Mahajan, K.; Coppola, D.; Chen, Y. A.; Zhu, W.; Lawrence, H. R.; Lawrence, N. J.; Mahajan, N. P., Ack1 Tyrosine Kinase Activation Correlates with Pancreatic Cancer Progression. Am J Pathol 2012, 180 (4), 1386-1393.
6. Chen, R.; Kim, O.; Yang, J.; Sato, K.; Eisenmann, K. M.; McCarthy, J.; Chen, H.; Qui, Y., Regulation of Akt/PKB activation by tyrosine phosphorylation. J Biol Chem 2001, 276 (34), 31858-31862.
7. Zheng, Y.; Peng, M.; Wang, Z.; Asara, J. M.; Tyner, A. L., Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor. Mol Cell Biol 2010, 30 (17), 4280-4292.
8. Ou, Y. H.; Torres, M.; Ram, R.; Formstecher, E.; Roland, C.; Cheng, T.; Brekken, R.; Wurz, R.; Tasker, A.; Polverino, T.; Tan, S. L.; White, M. A., TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 2011, 41 (4), 458-470.
9. Joung, S. M.; Park, Z. Y.; Rani, S.; Takeuchi, O.; Akira, S.; Lee, J. Y., Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol 2011, 186 (1), 499-507.
10. Guo, J. P.; Coppola, D.; Cheng, J. Q., IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J Biol Chem 2011, 286 (43), 37389-37398.
11. Xie, X.; Zhang, D.; Zhao, B.; Lu, M. K.; You, M.; Condorelli, G.; Wang, C. Y.; Guan, K. L., IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A 2011, 108 (16), 6474-6479.
12. Bozulic, L.; Suracu, B.; Hynx, D.; Hemmings, B. A., PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 2008, 30 (2), 203-213. (Pubitemid 351626686)
13. Siddle, K., Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 2011, 47 (1), R1-10.
14. Zoncu, R.; Efeyan, A.; Sabatini, D. M., mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011, 12 (1), 21-35.
15. Sengupta, S.; Peterson, T. R.; Sabatini, D. M., Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010, 40 (2), 310-322.
16. Cheng, Z.; Tseng, Y.; White, M. F., Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab 2010, 21 (10), 589-598.
17. 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 (21), 5657-5670.
18. Zhang, X.; Tang, N.; Hadden, T. J.; Rishi, A. K., Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 2011, 1813 (11), 1978-1986.
19. Chen, C. C.; Jeon, S. M.; Bhaskar, P. T.; Nogueira, V.; Sundararajan, D.; Tonic, I.; Park, Y.; Hay, N., FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010, 18 (4), 592-604.
20. Liu, L. Z.; Parent, C. A., Review series: TOR kinase complexes and cell migration. J Cell Biol 2011, 194 (6), 815-824.
21. Wang, R. H.; Kim, H. S.; Xiao, C.; Xu, X.; Gavrilova, O.; Deng, C. X., Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 2011, 121 (11), 4477-4490.
22. Zinzalla, V.; Stracka, D.; Oppliger, W.; Hall, M. N., Activation of mTORC2 by association with the ribosome. Cell 2011, 144 (5), 757-768.
23. Assmann, A.; Ueki, K.; Wnnay, J. N.; Kadowaki, T.; Kulkarni, R. N., Glucose effects on beta-cell growth and survival require activation of insulin receptors and insulin receptor substrate 2. Mol Cell Biol 2009, 29 (11), 3219-3228.
24. Guha, M.; Fang, J. K.; Monks, R.; Birnbaum, M. J.; Avadhani, N. G., Activation of Akt is essential for the propagation of mitochondrial respiratory stress signaling and activation of the transcriptional coactivator heterogeneous ribonucleoprotein A2. Mol Biol Cell 2010, 21 (20), 3578-3589.
25. Smolková, K.; Plecitá-Hlavatá, L.; Bellance, N.; Benard, G.; Rossignol, R.; Ježek, P., Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 2011, 43 (7), 950-968.
26. Berardi, M. J.; Fantin, V. R., Survival of the fittest: metabolic adaptations in cancer. Curr Opin Genet Dev 2011, 21 (1), 59-66.
27. Robey, R. B.; Hay, N., Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 2009, 19 (1), 25-31.
28. Sun, Q.; Chen, X.; Ma, J.; Peng, H.; Wang, F.; Zha, X.; Wang, Y.; Jing, Y.; Yang, H.; Chen, R.; Chang, L.; Zhang, Y.; Onda, H.; Chen, T.; Wang, M. R.; Lu, Y.; You, H.; Kwiatkowski, D.; Zhang, H., Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci U S A 2011, 108 (10), 4129-4134.
29. Tato, I.; Bartrons, R.; Ventura, F.; Rosa, J. L., Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J Biol Chem 2011, 286 (8), 6128-6142.
30. Hsieh, A. C.; Truitt, M. L.; Ruggero, D., Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer 2011, 105 (3), 329-336.
31. Coloff, J. L.; Macintyre, A. N.; Nichols, A. G.; Liu, T.; Gallo, C. A.; Plas, D. R.; Rathmell, J. C., Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition. Cancer Res 2011, 71 (15), 5204-5013.
32. Amaravadi, R. K.; Lippincott-Schwartz, J.; Yin, X. M.; Weiss, W. A.; Takebe, N.; Timmer, W.; DiPaola, R. S.; Lotze, M. T.; White, E., Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011, 17 (4), 654-666.
33. Signore, M.; Ricci-Vitiani, L.; De Maria, R., Targeting apoptosis pathways in cancer stem cells. Cancer Lett 2011, Feb 9. [Epub ahead of print].
34. Kim, J.; Kundu, M.; Viollet, B.; Guan, K. L., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011, 13 (2), 132-141.
35. Santi, S. A.; Lee, H., Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells. PLoS One 2011, 6 (1), e14614.
36. Thomson, A. W.; Turnquist, H. R.; Raimondi, G., Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009, 9 (5), 324-337.
37. Powell, J. D.; Delgoffe, G. M., The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 2010, 33 (3), 301-311.
38. Araki, K.; Ellebedy, A. H.; Ahmed, R., TOR in the immune system. Curr Opin Cell Biol 2011, 23 (6), 707-715.
39. Finlay, D.; Cantrell, D. A., Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol 2011, 11 (2), 109-117.
40. Hand, T. W.; Cui, W.; Jung, Y. W.; Sefik, E.; Joshi, N. S.; Chandele, A.; Liu, Y.; Kaech, S. M., Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci U S A 2010, 107 (38), 16601-16606.
41. Macintyre, A. N.; Finlay, D.; Preston, G.; Sinclair, L. V.; Waugh, C. M.; Tamas, P.; Feijoo, C.; Okkenhaug, K.; Cantrell, D. A., Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 2011, 34 (2), 224-236.
42. Wan, Q.; Kozhaya, L.; ElHed, A.; Ramesh, R.; Carlson, T. J.; Djuretic, I. M.; Sundrud, M. S.; Unutmaz, D., Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells. J Exp Med 2011, 208 (9), 1875-1887.
43. Cho, H.; Thorvaldsen, J. L.; Chu, Q.; Feng, F.; Birnbaum, M. J., Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001, 276 (42), 38349-38352.
44. Garofalo, R. S.; Orena, S. J.; Rafidi, K.; Torchia, A. J.; Stock, J. L.; Hildebrandt, A. L.; Coskran, T.; Black, S. C.; Brees, D. J.; Wicks, J. R.; McNeish, J. D.; Coleman, K. G., Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Invest. 2003, 112 (2), 197-208. (Pubitemid 38056356)
45. Easton, R. M.; Cho, H.; Roovers, K.; Shineman, D. W.; Mizrahi, M.; Forman, M. S.; Lee, V. M.; Szabolcs, M.; de Jong, R.; Oltersdorf, T.; Ludwig, T.; Efstratiadis, A.; Birnbaum, M. J., Role for Akt3/protein kinase B gamma in attainment of normal brain size. Mol Biol Cell 2005, 25 (5), 1869-1878. (Pubitemid 40280150)
46. Gonzalez, E.; McGraw, T. E., The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 2009, 8 (16), 2502-2508.
47. Hay, N., Akt isoforms and glucose homeostasis -the leptin connection. Trends Endocrinol Metab 2011, 22 (2), 66-73.
48. Chen, W. S.; Peng, X. D.; Wang, Y.; Xu, P. Z.; Chen, M. L.; Luo, Y.; Jeon, S. M.; Coleman, K.; Haschek, W. M.; Bass, J.; Philipson, L. H.; Hay, N., Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice. Mol Cell Biol 2009, 29 (11), 3151-3162.
49. Buzzi, F.; Xu, L.; Zuellig, R. A.; Boller, S. B.; Spinas, G. A.; Hynx, D.; Chang, Z.; Yang, Z.; Hemmings, B. A.; Tschopp, O.; Niessen, M., Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass. Mol Cell Biol 2010, 30 (3), 601-612.
50. Endersby, R.; Zhu, X.; Hay, N.; Ellison, D. W.; Baker, S. J., Nonredundant functions for Akt isoforms in astrocyte growth and gliomagenesis in an orthotopic transplantation model. Cancer Res 2011, 71 (12), 4106-4116.
51. Irie, H.Y.; Pearline, R.; Grueneberg, D.; Hsia, M.; Ravichandran, P.; Kothari, N.; Natesan, S.; Brugge, J.S. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 2005, 171 (6), 1023-1034. (Pubitemid 41815834)
52. Yoeli-Lerner, M.; Yiu, G. K.; Rabinovitz, I.; Erhardt, P.; Jauliac, S.; Toker, A., Akt Blocks Breast Cancer Cell Motility and Invasion through the Transcription Factor NFAT. Molecular Cell 2005, 20 (4), 539-550. (Pubitemid 41668639)
53. George, S.; Rochford, J. J.; Wolfrum, C.; Gray, S. L.; Schinner, S.; Wilson, J. C.; Soos, M. A.; Murgatroyd, P. R.; Williams, R. M.; Acerini, C. L.; Dunger, D. B.; Barford, D.; Umpleby, A. M.; Wareham, N. J.; Davies, H. A.; Schafer, A. J.; Stoffel, M.; O'Rahilly, S.; Barroso, I., A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 2004, 304 (5675), 1325-1328. (Pubitemid 38697429)
54. Tan, K.; Kimber, W. A.; Luan, J.; Soos, M. A.; Semple, R. K.; Wareham, N. J.; O'Rahilly, S.; Barroso, I., Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Diabetes 2007, 56 (3), 714-719. (Pubitemid 46348472)
55. Harmon, B. T.; Devaney, S. A.; Gordish-Dressman, H.; Reeves, E. K.; Zhao, P.; Devaney, J. M.; Hoffman, E. P., Functional characterization of a haplotype in the AKT1 gene associated with glucose homeostasis and metabolic syndrome. Hum Genet 2010, 128 (6), 635-645.
56. Devaney, J. M.; Gordish-Dressman, H.; Harmon, B. T.; Bradbury, M. K.; Devaney, S. A.; Harris, T. B.; Thompson, P. D.; Clarkson, P. M.; Price, T. B.; Angelopoulos, T. J.; Gordon, P. M.; Moyna, N. M.; Pesca, L. S.; VIsich, P. S.; Zoeller, R. F.; Seip, R. L.; Seo, J.; Kim, B. H.; Tosi, L. L.; Garcia, M.; Li, R.; Zmuda, J. M.; Delmonico, M. J.; Lindsay, R. S.; Howard, B. V.; Kraus, W. E.; Hoffman, E. P., AKT1 polymorphisms are associated with risk for metabolic syndrome. Hum Genet 2011, 129 (2), 129-139.
57. Elghazi, L.; Weiss, A. J.; Barker, D. J.; Callaghan, J.; Staloch, L.; Sandgren, E. P.; Gannon, M.; Adsay, V. N.; Bernal-Mizrachi, E., Regulation of pancreas plasticity and malignant transformation by Akt signaling. Gastroenterology 2009, 136 (3), 1091-1103.
58. Stanger, B. Z.; Stiles, B.; Lauwers, G. Y.; Bardeesy, N.; Mendoza, M.; Wang, Y.; Greenwood, A.; Cheng, K. H.; McLaughlin, M.; Brown, D.; DePinho, R. A.; Wu, H.; Melton, D. A.; Dor, Y., Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell. 2005, 8 (3), 185-195. (Pubitemid 41317590)
59. Hill, R.; Calvopina, J. H.; Kim, C.; Wang, Y.; Dawson, D. W.; Donahue, T. R.; Dry, S.; Wu, H., PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res 2010, 70 (18), 7114-7124.
60. Wang, L.; Liu, Y.; Yan Lu, S.; Nguyen, K. T.; Schroer, S. A.; Suzuki, A.; Mak, T. W.; Gaisano, H.; Woo, M., Deletion of Pten in pancreatic ß-cells protects against deficient ß-cell mass and function in mouse models of type 2 diabetes. Diabetes 2010, 59 (12), 3117-3126.
61. Xu, X.; Ehdaie, B.; Ohara, N.; Yoshino, T.; Deng, C. X., Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene 2010, 29 (5), 674-686.
62. Yao, L. J.; McCormick, J. A.; Wang, J.; Yang, K. Y.; Kidwai, A.; Luca Colussi, G.; Boini, K. M.; Birnbaum, M. J.; Lang, F.; German, M. S.; Pearce, D., Novel Role for SGK3 in Glucose Homeostasis Revealed in SGK3/Akt2 Double-Null Mice. Mol Endocrinol 2011, 25 (12), 2106-2118.
63. Gu, Y.; Lindner, J.; Kumar, A.; Yuan, W.; Magnuson, M. A., Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 2011, 60 (3), 827-837.
64. Kumar, A.; Lawrence, J. C. J.; Jung, D. Y.; Ko, H. J.; Keller, S. R.; Kim, J. K.; Magnuson, M. A.; Harris, T. E., Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 2010, 59 (6), 1397-1406.
65. Veilleux, A.; Houde, V. P.; Bellmann, K.; Marette, A., Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Mol Endocrinol 2010, 24 (4), 766-778.
66. Alliouachene, S.; Tuttle, R. L.; Boumard, S.; Lapointe, T.; Berissi, S.; Germain, S.; Jaubert, F.; Tosh, D.; Birnbaum, M. J.; Pende, M., Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. J Clin Invest 2008, 118 (11), 3629-3638.
67. Hanahan, D.; Weinberg, R. A., Hallmarks of cancer: the next generation. Cell 2011, 144, (5) 646-674.
68. Altomare, D. A.; Testa, J. R., Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005, 24, (50) 7455-7464. (Pubitemid 41637985)
69. Delbaldo, C.; Albert, S.; Dreyer, C.; Sablin, M. P.; Serova, M.; Raymond, E.; Faivre, S., Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors. Target Oncol 2011, 6 (2), 119-124.
70. Slattery, M. L.; Herrick, J. S.; Lundgreen, A.; Fitzpatrick, F. A.; Curtin, K.; Wolff, R. K., Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis 2010, 31 (9), 1604-1611.
71. Slattery, M. L.; Lundgreen, A.; Herrick, J. S.; Wolff, R. K., Genetic variation in RPS6KA1, RPS6KA2, RPS6KB1, RPS6KB2, and PDK1 and risk of colon or rectal cancer. Mutat Res 2011, 706 (1-2), 13-20.
72. Pu, X.; Hildebrandt, M. A.; Lu, C.; Lin, J.; Stewart, D. J.; Ye, Y.; Gu, J.; Spitz, M. R.; Wu, X., PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy. Lung Cancer 2011, 71 (1), 82-88.
73. Lin, J.; Wang, J.; Greisinger, A. J.; Grossman, H. B.; Forman, M. R.; Dinney, C. P.; Hawk, E. T.; Wu, X., Energy balance, the PI3K-AKT-mTOR pathway genes, and the risk of bladder cancer. Cancer Prev Res (Phila) 2010, 3 (4), 505-517.
74. Gulhati, P.; Bowen, K. A.; Liu, J.; Stevens, P. D.; Rychahou, P. G.; Chen, M.; Lee, E. Y.; Weiss, H. L.; O'Connor, K. L.; Gao, T.; Evers, B. M., mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011, 71 (9), 3246-3256.
75. Goncharova, E. A.; Goncharov, D. A.; Li, H.; Pimtong, W.; Lu, S.; Khavin, I.; Krymskaya, V. P., mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol 2011, 31 (12), 2484-2498.
76. Kim, E. K.; Yun, S. J.; Ha, J. M.; Kim, Y. W.; Jin, I. H.; Yun, J.; Shin, H. K.; Song, S. H.; Kim, J. H.; Lee, J. S.; Kim, C. D.; Bae, S. S., Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Oncogene 2011, 30 (26), 2954-2963.
77. Chappell, W. H.; Steelman, L. S.; Long, J. M.; Kempf, R. C.; Abrams, S. L.; Franklin, R. A.; Bäsecke, J.; Stivala, F.; Donia, M.; Fagone, P.; Malaponte, G.; Mazzarino, M. C.; Nicoletti, F.; Libra, M.; Maksimovic-Ivanic, D.; Mijatovic, S.; Montalto, G.; Cervello, M.; Laidler, P.; Milella, M.; Tafuri, A.; Bonati, A.; Evangelisti, C.; Cocco, L.; Martelli, A. M.; McCubrey, J. A., Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011, 2 (3), 135-164.
78. McCubrey, J. A.; Steelman, L. S.; Kempf, C. R.; Chappell, W. H.; Abrams, S. L.; Stivala, F.; Malaponte, G.; Nicoletti, F.; Libra, M.; Bäsecke, J.; Maksimovic-Ivanic, D.; Mijatovic, S.; Montalto, G.; Cervello, M.; Cocco, L.; Martelli, A. M., Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol 2011, 226 (11), 2762-2781.
79. Carew, J. S.; Kelly, K. R.; Nawrocki, S. T., Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 2011, 6 (1), 17-27.
80. Zhang, Y. J.; Duan, Y.; Zheng, X. F., Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 2011, 16 (7-8), 325-331.
81. Mazzoletti, M.; Bortolin, F.; Brunelli, L.; Pastorelli, R.; Di Giandomenico, S.; Erba, E.; Ubezio, P.; Broggini, M., Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res 2011, 71 (13), 4573-4584.
82. Fan, Q. W.; Cheng, C.; Hackett, C.; Feldman, M.; Houseman, B. T.; Nicolaides, T.; Haas-Kogan, D.; James, C. D.; Oakes, S. A.; Debnath, J.; Shokat, K. M.; Weiss, W. A., Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010, 3 (147), ra81.
83. Huang, S.; Yang, Z. J.; Yu, C.; Sinicrope, F. A., Inhibition of mTOR Kinase by AZD8055 Can Antagonize Chemotherapy-induced Cell Death through Autophagy Induction and Down-regulation of p62/Sequestosome 1. J Biol Chem 2011, 286 (46), 40002-40012.
84. Green, D. R.; Galluzzi, L.; Kroemer, G., Mitochondria and the autophagyinflammation-cell death axis in organismal aging. Science 2011, 333 (6046), 1109-1112.
85. Howell, J. J.; Manning, B. D., mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab 2011, 22 (3), 94-102.
86. Rubinsztein, D. C.; Mariño, G.; Kroemer, G., Autophagy and aging. Cell 2011, 146 (5), 682-695.
87. Kenyon, C. J., The genetics of ageing. Nature 2010, 464 (7288), 504-512.
88. Bjedov, I.; Toivonen, J. M.; Kerr, F.; Slack, C.; Jacobson, J.; Foley, A.; Partridge, L., Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010, 11 (1), 35-46.
89. Harrison, D. E.; Strong, R.; Sharp, Z. D.; Nelson, J. F.; Astle, C. M.; Flurkey, K.; Nadon, N. L.; Wilkinson, J. E.; Frenkel, K.; Carter, C. S.; Pahor, M.; Javors, M. A.; Fernandez, E.; Miller, R. A., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460 (7253), 392-395.
90. Kapahi, P.; Chen, D.; Rogers, A. N.; Katewa, S. D.; Li, P. W.; Thomas, E. L.; Kockel, L., With TOR, less is more: a key role for the conserved nutrientsensing TOR pathway in aging. Cell Metab 2010, 11 (6), 453-465.
91. McCurdy, C. E.; Cartee, G. D., Akt2 is essential for the full effect of calorie restriction on insulin-stimulated glucose uptake in skeletal muscle. Diabetes 2005, 54 (5), 1349-1356. (Pubitemid 40586663)
92. Moore, T.; Checkley, L. A.; DiGiovanni, J., Dietary energy balance modulation of epithelial carcinogenesis: a role for IGF-1 receptor signaling and crosstalk. Ann N Y Acad Sci 2011, 1229, 7-17.
93. Sharp, Z. D.; Richardson, A., Aging and cancer: can mTOR inhibitors kill two birds with one drug? Target Oncol 2011, 6 (1), 41-51.
94. Lashinger, L. M.; Malone, L. M.; Brown, G. W.; Daniels, E. A.; Goldberg, J. A.; Otto, G.; Fischer, S. M.; Hursting, S. D., Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res (Phila) 2011, 4 (7), 1041-1051.
95. Youngblood, B.; Davis, C. W.; Ahmed, R., Making memories that last a lifetime: heritable functions of self-renewing memory CD8 T cells. Int Immunol 2010, 22 (10), 797-803.
96. Lee, K.; Gudapati, P.; Dragovic, S.; Spencer, C.; Joyce, S.; Killeen, N.; Magnuson, M. A.; Boothby, M., Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010, 32 (6), 743-753.
97. Li, Q.; Rao, R. R.; Araki, K.; Pollizzi, K.; Odunsi, K.; Powell, J. D.; Shrikant, P. A., A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 2011, 34 (4), 541-553.
98. Rao, R. R.; Li, Q.; Odunsi, K.; Shrikant, P. A., The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 2010, 32 (1), 67-78.
99. Rao, R. R.; Li, Q.; Shrikant, P. A., Fine-tuning CD8(+) T cell functional responses: mTOR acts as a rheostat for regulating CD8(+) T cell proliferation, survival and differentiation? Cell Cycle 2010, 9 (15), 2996-3001.
100. Koido, S.; Homma, S.; Takahara, A.; Namiki, Y.; Tsukinaga, S.; Mitobe, J.; Odahara, S.; Yukawa, T.; Matsudaira, H.; Nagatsuma, K.; Uchiyama, K.; Satoh, K.; Ito, M.; Komita, H.; Arakawa, H.; Ohkusa, T.; Gong, J.; Tajiri, H., Current immunotherapeutic approaches in pancreatic cancer. Clin Dev Immunol 2011, 2011, 267539.
101. Jiang, Q.; Weiss, J. M.; Back, T.; Chan, T.; Ortaldo, J. R.; Guichard, S.; Wiltrout, R. H., mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res 2011, 71 (12), 4074-4084.
102. Kittipatarin, C.; Khaled, A. R., Interlinking Interleukin-7. Cytokine 2007, 39 (1), 75-83. (Pubitemid 47446258)
103. Chetoui, N.; Boisvert, M.; Gendron, S.; Aoudjit, F., Interleukin-7 promotes the survival of human CD4+ effector/memory T cells by up-regulating Bcl-2 proteins and activating the JAK/STAT signalling pathway. Immunology 2010, 130 (3), 418-426.
104. Zhang, Y.; Pfannenstiel, L. W.; Bolesta, E.; Montes, C. L.; Zhang, X.; Chapoval, A. I.; Gartenhaus, R. B.; Strome, S. E.; Gastman, B. R., Interleukin-7 inhibits tumor-induced CD27-CD28-suppressor T cells: implications for cancer immunotherapy. Clin Cancer Res 2011, 17 (15), 4975-4986.
105. O'Brien, T. F.; Gorentla, B. K.; Xie, D.; Srivatsan, S.; McLeod, I. X.; He, Y. W.; Zhong, X. P., Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol 2011, 41 (11), 3361-3370.
106. Yang, K.; Neale, G.; Green, D. R.; He, W.; Chi, H., The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 2011, 12 (9), 888-897.
107. Cho, D. C.; Cohen, M. B.; Panka, D. J.; Collins, M.; Ghebremichael, M.; Atkins, M. B.; Signoretti, S.; Mier, J. W., The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 2010, 16 (14), 3628-3638.