MTORC1 signaling and regulation of pancreatic β-cell mass

Cell Cycle

Volumn 11, Issue 10, 2012, Pages 1892-1902

  Blandino Rosano, Manuel ^a   Chen, Angela Y ^a   Scheys, Joshua O ^a   Alejandro, Emilyn U ^a   Gould, Aaron P ^b   Taranukha, Tatyana ^b   Elghazi, Lynda ^a   Cras Méneur, Corentin ^a   Bernal Mizrachi, Ernesto ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AKT; Cell cycle; Glucose homeostasis; Insulin; Islets and proliferation; mTORC1; S6K; TSC1; TSC2; cells; cell signaling

Indexed keywords

AURORA A KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PARAFORMALDEHYDE; PROLINE RICH PROTEIN; PROTEIN KINASE B; RHEB PROTEIN; TARGET OF RAPAMYCIN KINASE; TUBERIN;

ADIPOCYTE; AGING; CELL GROWTH; CELL PROLIFERATION; CELL SIZE; CELL SURVIVAL; GENE DELETION; GENETIC TRANSCRIPTION; GLUCOSE TOLERANCE; HUMAN; HYPERINSULINEMIA; HYPERPHAGIA; HYPERTROPHY; HYPOXIA; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; INSULINOMA; NERVE CELL PLASTICITY; OBESITY; PANCREAS ISLET BETA CELL; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS; RAPTOR; REVIEW; RNA TRANSLATION; SIGNAL TRANSDUCTION;

ANIMALIA;

EID: 84861408377     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.20036     Document Type: Review

References (111)

1. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431:200-5; PMID:15306821; http://dx.doi.org/ 10.1038/ nature02866.
2. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance and cell survival deficiencies. Curr Biol 2004; 14:1650- 6; PMID:15380067; http://dx.doi.org/10.1016/j. cub.2004.08.026.
3. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004; 166:213- 23; PMID:15249583; http://dx.doi.org/10.1083/ jcb.200403069.
4. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 2005; 146:1473- 81; PMID:15604215; http://dx.doi.org/10.1210/ en.2004-0921.
5. Asahara S, Matsuda T, Kido Y, Kasuga M. Increased ribosomal biogenesis induces pancreatic beta cell failure in mice model of type 2 diabetes. Biochem Biophys Res Commun 2009; 381:367- 71; PMID:19309774; http://dx.doi.org/10.1016/ j. bbrc.2009.02.047.
6. Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem 2005; 280:2282-93; PMID:15537654; http://dx.doi. org/10.1074/jbc.M412179200.
7. Rachdi L, Balcazar N, Osorio-Duque F, Elghazi L, Weiss AJ, Gould AP, et al. Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci USA 2008; 105:9250- 5; PMID:18587048; http://dx.doi.org/10.1073/ pnas.0803047105.
8. Shigeyama Y, Kobayashi T, Kido Y, Hashimoto N, Asahara S, Matsuda T, et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol 2008; 28:2971- 9; PMID:18316403; http://dx.doi.org/10.1128/ MCB.01695-07.
9. Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008; 57:945-57; PMID:18174523; http://dx.doi.org/10.2337/db07- 0922.
10. Liu H, Remedi MS, Pappan KL, Kwon G, Rohatgi N, Marshall CA, et al. Both Glycogen Synthase Kinase-3 (GSK-3) and Mammalian Target of Rapamycin (mTOR) Pathways Contribute to DNA Synthesis, Cell Cycle Progression and Proliferation in Human Islets. Diabetes 2008; PMID:19073772; http://dx.doi.org/10.2337/db07- 1208.
11. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24:6710- 8; PMID:15254238; http://dx.doi.org/10.1128/ MCB.24.15.6710-6718.2004.
12. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycininsensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14:1296- 302; PMID:15268862; http://dx.doi.org/10.1016/j. cub.2004.06.054.
13. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6:1122-8; PMID:15467718; http://dx.doi.org/10. 1038/ncb1183.
14. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163-75; PMID:12150925; http://dx.doi. org/10.1016/S0092-8674(02)00808-5.
15. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007; 9:316-23; PMID:17277771; http://dx.doi. org/10.1038/ncb1547.
16. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307:1098- 101; PMID:15718470; http://dx.doi.org/10.1126/ science.1106148.
17. Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, et al. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 2000; 19:6306-16; PMID:11175345; http://dx.doi. org/10.1038/sj.onc.1204009.
18. Chong-Kopera H, Inoki K, Li Y, Zhu T, Garcia- Gonzalo FR, Rosa JL, et al. TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J Biol Chem 2006; 281:8313-6; PMID:16464865; http://dx.doi. org/10.1074/jbc.C500451200.
19. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. 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; 10:151-62; PMID:12150915; http://dx.doi.org/10.1016/S1097-2765(02)00568-3.
20. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648-57; PMID:12172553; http://dx.doi.org/10.1038/ncb839.
21. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 2003; 112:1223-33; PMID:14561707.
22. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11:1457- 66; PMID:12820960; http://dx.doi.org/10.1016/ S1097-2765(03)00220-X.
23. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115:577-90; PMID:14651849; http:// dx.doi.org/10.1016/S0092-8674(03)00929-2.
24. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, et al. Phosphatidylinositol-3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002; 277:35364-70; PMID:12167664; http://dx.doi.org/10.1074/jbc.M205838200.
25. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126:955- 68; PMID:16959574; http://dx.doi.org/10.1016/j. cell.2006.06.055.
26. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008; 10:935- 45; PMID:18604198; http://dx.doi.org/10.1038/ ncb1753.
27. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008; 320:1496-501; PMID:18497260; http://dx.doi.org/10.1126/science. 1157535.
28. Findlay GM, Yan L, Procter J, Mieulet V, Lamb RFA. A MAP4 kinase related to Ste20 is a nutrientsensitive regulator of mTOR signalling. Biochem J 2007; 403:13-20; PMID:17253963; http://dx.doi. org/10.1042/BJ20061881.
29. Byfield MP, Murray JT, Backer JM. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 2005; 280:33076- 82; PMID:16049009; http://dx.doi.org/10.1074/jbc. M507201200.
30. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, et al. Amino acids mediate mTOR/ raptor signaling through activation of class 3-phosphatidylinositol-3OH-kinase. Proc Natl Acad Sci USA 2005; 102:14238-43; PMID:16176982; http:// dx.doi.org/10.1073/pnas.0506925102.
31. Reiling JH, Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 2004; 18:2879-92; PMID:15545626; http://dx.doi.org/10.1101/gad.322704.
32. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:2893-904; PMID:15545625; http://dx.doi. org/10.1101/gad.1256804.
33. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30:214-26; PMID:18439900; http:// dx.doi.org/10.1016/j.molcel.2008.03.003.
34. Zheng M, Wang YH, Wu XN, Wu SQ, Lu BJ, Dong MQ, et al. Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletioninduced suppression of mTORC1. Nat Cell Biol 2011; 13:263-72; PMID:21336308; http://dx.doi. org/10.1038/ncb2168.
35. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12:9-22; PMID:17613433; http://dx.doi.org/10.1016/j. ccr.2007.05.008.
36. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18:1926-45; PMID:15314020; http://dx.doi.org/10.1101/ gad.1212704.
37. Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE 2003; 2003:15; PMID:14668532; http:// dx.doi.org/10.1126/stke.2122003re15.
38. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 2002; 16:1472-87; PMID:12080086; http:// dx.doi.org/10.1101/gad.995802.
39. Weber JD, Gutmann DH. Deconvoluting mTOR biology. Cell Cycle 2012; 11:236-48; PMID:22214661; http://dx.doi.org/10.4161/cc.11.2.19022.
40. Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 2012; 441:1- 21; PMID:22168436; http://dx.doi.org/10.1042/ BJ20110892.
41. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J 2004; 23:1761- 9; PMID:15071500; http://dx.doi.org/10.1038/ sj.emboj.7600193.
42. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J 2006; 25:2781-91; PMID:16763566; http://dx.doi. org/10.1038/sj.emboj.7601166.
43. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 2001; 20:4370-9; PMID:11500364; http://dx.doi. org/10.1093/emboj/20.16.4370.
44. Richardson CJ, Bröenstrup M, Fingar DC, Jülich K, Ballif BA, Gygi S, et al. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol 2004; 14:1540-9; PMID:15341740; http://dx.doi. org/10.1016/j.cub.2004. 08.061.
45. Wilson KF, Wu WJ, Cerione RA. Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex. J Biol Chem 2000; 275:37307-10; PMID:10973943; http://dx.doi.org/10.1074/jbc. C000482200.
46. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001; 276:38052-60; PMID:11498541.
47. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167:399-403; PMID:15533996; http:// dx.doi.org/10.1083/jcb.200408161.
48. Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N, et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 1994; 266:653-6; PMID:7939721; http://dx.doi.org/10.1126/ science.7939721.
49. Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC Jr, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature 1994; 371:762-7; PMID:7935836; http://dx.doi. org/10.1038/371762a0.
50. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004; 24:200-16; PMID:14673156; http://dx.doi.org/10.1128/MCB.24.1.200-216.2004.
51. Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F, Richard D, Cianflone K, et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest 2007; 117:387-96; PMID:17273556; http://dx.doi. org/10.1172/JCI29528.
52. Polak P, Cybulski N, Feige JN, Auwerx J, Rüegg MA, Hall MN. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 2008; 8:399-410; PMID:19046571; http://dx.doi.org/10.1016/j.cmet.2008.09.003.
53. Bentzinger CF, Romanino K, Cloëtta D, Lin S, Mascarenhas JB, Oliveri F, et al. Skeletal musclespecific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 2008; 8:411-24; PMID:19046572; http://dx.doi.org/10.1016/j.cmet.2008.10.002.
54. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010; 468:1100-4; PMID:21179166; http://dx.doi. org/10.1038/nature09584.
55. Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 2011; 60:827-37; PMID:21266327; http:// dx.doi.org/10.2337/db10-1194.
56. Zhang N, Su D, Qu S, Tse T, Bottino R, Balamurugan AN, et al. Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes 2006; 55:2429-36; PMID:16936190; http://dx.doi.org/10.2337/db06-0173.
57. Bell E, Cao X, Moibi JA, Greene SR, Young R, Trucco M, et al. Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes 2003; 52:2731-9; PMID:14578291; http://dx.doi. org/10.2337/diabetes.52.11.2731.
58. Shimodahira M, Fujimoto S, Mukai E, Nakamura Y, Nishi Y, Sasaki M, et al. Rapamycin impairs metabolism- secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism. J Endocrinol 2010; 204:37-46; PMID:19812126; http://dx.doi. org/10.1677/JOE-09-0216.
59. Johnson JD, Ao Z, Ao P, Li H, Dai LJ, He Z, et al. Different effects of FK506, rapamycin and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant 2009; 18:833-45; PMID:19500470; http://dx.doi. org/10.3727/096368909X471198.
60. Balcazar N, Sathyamurthy A, Elghazi L, Gould A, Weiss A, Shiojima I, et al. mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J Biol Chem 2009; 284:7832-42; PMID:19144649; http:// dx.doi.org/10.1074/jbc.M807458200.
61. Zahr E, Molano RD, Pileggi A, Ichii H, Jose SS, Bocca N, et al. Rapamycin impairs in vivo proliferation of islet beta-cells. Transplantation 2007; 84:1576-83; PMID:18165767; http://dx.doi. org/10.1097/01.tp.0000296035.48728.28.
62. Niclauss N, Bosco D, Morel P, Giovannoni L, Berney T, Parnaud G. Rapamycin impairs proliferation of transplanted islet β cells. Transplantation 2011; 91:714-22; PMID:21297554.
63. Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16:3128- 35; PMID:16107580; http://dx.doi.org/10.1681/ ASN.2005050487.
64. Di Paolo S, Teutonico A, Leogrande D, Capobianco C, Schena PF. Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes? J Am Soc Nephrol 2006; 17:2236-44; PMID:16807405; http://dx.doi.org/ 10.1681/ASN.2006030196.
65. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460:392-5; PMID:19587680.
66. Veilleux A, Houde VP, 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; 24:766- 78; PMID:20203102; http://dx.doi.org/10.1210/ me.2009-0328.
67. Choo AY, Blenis J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009; 8:567- 72; PMID:19197153; http://dx.doi.org/10.4161/ cc.8.4.7659.
68. Hamada S, Hara K, Hamada T, Yasuda H, Moriyama H, Nakayama R, et al. Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic betacells leads to increased beta-cell mass and prevention of hyperglycemia. Diabetes 2009; 58:1321-32; PMID:19258434; http://dx.doi.org/10.2337/db08- 0519.
69. Gao X, Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 2001; 15:1383-92; PMID:11390358; http:// dx.doi.org/10.1101/gad.901101.
70. Potter CJ, Pedraza LG, Huang H, Xu T. The tuberous sclerosis complex (TSC) pathway and mechanism of size control. Biochem Soc Trans 2003; 31:584- 6; PMID:12773160; http://dx.doi.org/10.1042/ BST0310584.
71. Matsumoto S, Bandyopadhyay A, Kwiatkowski DJ, Maitra U, Matsumoto T. Role of the Tsc1-Tsc2 complex in signaling and transport across the cell membrane in the fission yeast Schizosaccharomyces pombe. Genetics 2002; 161:1053-63; PMID:12136010.
72. Mori H, Inoki K, Opland D, Münzberg H, Villanueva EC, Faouzi M, et al. Critical roles for the TSC-mTOR pathway in β-cell function. Am J Physiol Endocrinol Metab 2009; 297:1013-22; PMID:19690069; http://dx.doi.org/10. 1152/ajpendo. 00262.2009.
73. Mori H, Inoki K, Münzberg H, Opland D, Faouzi M, Villanueva EC, et al. Critical role for hypothalamic mTOR activity in energy balance. Cell Metab 2009; 9:362-74; PMID:19356717; http://dx.doi. org/10.1016/j.cmet.2009.03.005.
74. Wicksteed B, Brissova M, Yan W, Opland DM, Plank JL, Reinert RB, et al. Conditional gene targeting in mouse pancreatic β-Cells: analysis of ectopic Cre transgene expression in the brain. Diabetes 2010; 59:3090-8; PMID:20802254; http://dx.doi. org/10.2337/db10-0624.
75. Dowling RJO, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, et al. mTORC1- mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 2010; 328:1172- 6; PMID:20508131; http://dx.doi.org/10. 1126/science. 1187532.
76. Elghazi L, Balcazar N, Blandino-Rosano M, Cras- Méneur C, Fatrai S, Gould AP, et al. Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in betacells. Diabetes 2010; 59:2390-9; PMID:20622167; http://dx.doi.org/10.2337/db09-0851.
77. Beretta L, Gingras AC, Svitkin YV, Hall MN, Sonenberg N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 1996; 15:658-64; PMID:8599949.
78. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 1998; 273:14484-94; PMID:9603962; http:// dx.doi.org/10.1074/jbc.273.23.14484.
79. Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, et al. ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Cell Metab 2008; 7:269-76; PMID:18316032; http:// dx.doi.org/10.1016/j.cmet.2008.01.008.
80. Xu G, Kwon G, Marshall CA, Lin TA, Lawrence JC Jr, McDaniel ML. Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. J Biol Chem 1998; 273:28178-84; PMID:9774438; http:// dx.doi.org/10.1074/jbc.273.43.28178.
81. Xu G, Marshall CA, Lin TA, Kwon G, Munivenkatappa RB, Hill JR, et al. Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. An insulin-receptor mechanism for autoregulation of protein synthesis by translation. J Biol Chem 1998; 273:4485-91; PMID:9468502; http://dx.doi.org/10. 1074/jbc.273.8.4485.
82. Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML. Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes 2001; 50:353-60; PMID:11272147; http://dx.doi.org/10.2337/diabetes. 50.2.353.
83. Kwon G, Marshall CA, Pappan KL, Remedi MS, McDaniel ML. Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins and growth factors in islets. Diabetes 2004; 53:225- 32; PMID:15561916; http://dx.doi.org/10.2337/diabetes. 53.suppl-3.S225.
84. Bidinosti M, Ran I, Sanchez-Carbente MR, Martineau Y, Gingras AC, Gkogkas C, et al. Postnatal deamidation of 4E-BP2 in brain enhances its association with raptor and alters kinetics of excitatory synaptic transmission. Mol Cell 2010; 37:797- 808; PMID:20347422; http://dx.doi.org/10.1016/j. molcel.2010.02.022.
85. Kimball SR, Jefferson LS. Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin. Curr Opin Clin Nutr Metab Care 2004; 7:39-44; PMID:15090902; http://dx.doi.org/10.1097/00075197- 200401000- 00008.
86. Um SH, D'Alessio D, Thomas G. Nutrient overload, insulin resistance and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006; 3:393-402; PMID:16753575; http://dx.doi.org/10.1016/j. cmet.2006.05.003.
87. Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, et al. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 2000; 408:994-7; PMID:11140689; http://dx.doi. org/10.1038/35050135.
88. Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 1998; 17:6649- 59; PMID:9822608; http://dx.doi.org/10.1093/ emboj/17.22.6649.
89. Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C, White MF. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab 2010; 11:84- 92; PMID:20074531; http://dx.doi.org/10.1016/j. cmet.2009.11.003.
90. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, et al. S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004; 24:3112- 24; PMID:15060135; http://dx.doi.org/10.1128/ MCB.24.8.3112-3124.2004.
91. Alliouachene S, Tuttle RL, Boumard S, Lapointe T, Berissi S, Germain S, et al. Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. J Clin Invest 2008; 118:3629- 38; PMID:18846252; http://dx.doi.org/10.1172/ JCI35237.
92. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, et al. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 2005; 19:2199-211; PMID:16166381; http://dx.doi.org/10. 1101/ gad.351605.
93. Cota D, Matter EK, Woods SC, Seeley RJ. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci 2008; 28:7202-8; PMID:18614690; http://dx.doi. org/10.1523/JNEUROSCI. 1389-08.2008.
94. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429:41-6; PMID:15129273; http://dx.doi. org/10.1038/nature02520.
95. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391:900-4; PMID:9495343; http://dx.doi.org/10.1038/36116.
96. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 1999; 23:32-40; PMID:10471495; http://dx.doi.org/10.1038/ 12631.
97. Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest 2003; 112:1521-32; PMID:14617753.
98. Lingohr MK, Dickson LM, McCuaig JF, Hugl SR, Twardzik DR, Rhodes CJ. Activation of IRS-2-mediated signal transduction by IGF-1, but not TGFalpha or EGF, augments pancreatic beta-cell proliferation. Diabetes 2002; 51:966-76; PMID:11916914; http://dx.doi.org/10.2337/diabetes. 51.4.966.
99. Lingohr MK, Dickson LM, Wrede CE, Briaud I, McCuaig JF, Myers MG Jr, et al. Decreasing IRS-2 expression in pancreatic beta-cells (INS-1) promotes apoptosis, which can be compensated for by introduction of IRS-4 expression. Mol Cell Endocrinol 2003; 209:17-31; PMID:14604813; http://dx.doi. org/10.1016/j.mce.2003.08.003.
100. Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun 2004; 313:443- 6; PMID:14684182; http://dx.doi.org/10.1016/j. bbrc.2003.07.019.
101. Meijer AJ, Dubbelhuis PF. Amino acid signalling and the integration of metabolism. Biochem Biophys Res Commun 2004; 313:397-403; PMID:14684175; http://dx.doi.org/10.1016/j.bbrc.2003.07.012.
102. Miloloza A, Kubista M, Rosner M, Hengstschläger M. Evidence for separable functions of tuberous sclerosis gene products in mammalian cell cycle regulation. J Neuropathol Exp Neurol 2002; 61:154-63; PMID:11853018.
103. Soucek T, Rosner M, Miloloza A, Kubista M, Cheadle JP, Sampson JR, et al. Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression. Oncogene 2001; 20:4904-9; PMID:11521203; http://dx.doi. org/10.1038/sj.onc.1204627.
104. Hengstschläger M, Rodman DM, Miloloza A, Hengstschläger-Ottnad E, Rosner M, Kubista M. Tuberous sclerosis gene products in proliferation control. Mutat Res 2001; 488:233-9; PMID:11397651; http://dx.doi.org/10.1016/ S1383-5742(01)00058-8.
105. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471- 84; PMID:16469695; http://dx.doi.org/10.1016/j. cell.2006.01.016.
106. Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005; 19:1773-8; PMID:16027169; http://dx.doi.org/10.1101/gad. 1314605.
107. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007; 128:309-23; PMID:17254969; http:// dx.doi.org/10.1016/j. cell.2006.12.029.
108. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001; 276:38052-60; PMID:11498541.
109. Krebs M, Brunmair B, Brehm A, Artwohl M, Szendroedi J, Nowotny P, et al. The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 2007; 56:1600-7; PMID:17329620; http://dx.doi.org/10. 2337/db06- 1016.
110. Ueno M, Carvalheira JBC, Tambascia RC, Bezerra RMN, Amaral ME, Carneiro EM, et al. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/ p70 S6K pathway. Diabetologia 2005; 48:506- 18; PMID:15692808; http://dx.doi.org/10.1007/ s00125-004-1662-6.
111. Abe Y, Yoon SO, Kubota K, Mendoza MC, Gygi SP, Blenis J. p90 ribosomal S6 kinase and p70 ribosomal S6 kinase link phosphorylation of the eukaryotic chaperonin containing TCP-1 to growth factor, insulin and nutrient signaling. J Biol Chem 2009; 284:14939-48; PMID:19332537; http://dx.doi. org/10.1074/jbc. M900097200.