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Cell Cycle Regulation by the Nutrient-Sensing Mammalian Target of Rapamycin (mTOR) Pathway

  • Elisabet Cuyàs
  • Bruna Corominas-Faja
  • Jorge Joven
  • Javier A. Menendez
Part of the Methods in Molecular Biology book series (MIMB, volume 1170)

Abstract

Cell division involves a series of ordered and controlled events that lead to cell proliferation. Cell cycle progression implies not only demanding amounts of cell mass, protein, lipid, and nucleic acid content but also a favorable energy state. The mammalian target of rapamycin (mTOR), in response to the energy state, nutrient status, and growth factor stimulation of cells, plays a pivotal role in the coordination of cell growth and the cell cycle. Here, we review how the nutrient-sensing mTOR-signaling cascade molecularly integrates nutritional and mitogenic/anti-apoptotic cues to accurately coordinate cell growth and cell cycle. First, we briefly outline the structure, functions, and regulation of the mTOR complexes (mTORC1 and mTORC2). Second, we concisely evaluate the best known ability of mTOR to control G1-phase progression. Third, we discuss in detail the recent evidence that indicates a new genome stability caretaker function of mTOR based on the specific ability of phosphorylated forms of several mTOR-signaling components (AMPK, raptor, TSC, mTOR, and S6K1), which spatially and temporally associate with essential mitotic regulators at the mitotic spindle and at the cytokinetic cleavage furrow.

Key words

Cell cycle mTOR mTORC Nutrients Energy status Mitosis AMPK Raptor S6K1 

Notes

Acknowledgements

This work was supported financially by grants CP05-00090, PI06-0778, and RD06-0020-0028 from the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain; the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Spain); and the Ministerio de Ciencia e Innovación (SAF2009-11579 and SAF2012-389134, Plan Nacional de I + D + I, MICINN, Spain).

References

  1. 1.
    Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166PubMedGoogle Scholar
  2. 2.
    Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81(3):323–330PubMedGoogle Scholar
  3. 3.
    Cobrinik D (2005) Pocket proteins and cell cycle control. Oncogene 24 (17):2796–2809Google Scholar
  4. 4.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512PubMedGoogle Scholar
  5. 5.
    Barbash O, Diehl JA (2008) Regulation of the cell cycle. In: Mendelsohn J, Howley PM, Israel MA, Gray JW, Thompson CB (eds) The molecular basis of cancer, 3rd edn. WB Saunders, Philadelphia, PA, pp 177–188Google Scholar
  6. 6.
    Massagué J (2004) G1 cell-cycle control and cancer. Nature 432(7015):298–306PubMedGoogle Scholar
  7. 7.
    Santoni-Rugiu E, Falck J, Mailand N, Bartek J, Lukas J (2000) Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the pRb/E2F pathway. Mol Cell Biol 20(10):3497–3509PubMedCentralPubMedGoogle Scholar
  8. 8.
    Stark GR, Taylor WR (2006) Control of the G2/M transition. Mol Biotechnol 32(3):227–248PubMedGoogle Scholar
  9. 9.
    Pyronnet S, Sonenberg N (2001) Cell-cycle-dependent translational control. Curr Opin Genet Dev 11(1):13–18PubMedGoogle Scholar
  10. 10.
    Pyronnet S, Dostie J, Sonenberg N (2001) Suppression of cap-dependent translation in mitosis. Genes Dev 15(16):2083–2093PubMedCentralPubMedGoogle Scholar
  11. 11.
    Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7(9):644–656PubMedGoogle Scholar
  12. 12.
    Horn HF, Vousden KH (2007) Coping with stress: multiple ways to activate p53. Oncogene 26(9):1306–1316PubMedGoogle Scholar
  13. 13.
    Baus F, Gire V, Fisher D, Piette J, Dulić V (2003) Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. EMBO J 22(15):3992–4002PubMedCentralPubMedGoogle Scholar
  14. 14.
    Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253(5022):905–909PubMedGoogle Scholar
  15. 15.
    Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596PubMedGoogle Scholar
  16. 16.
    Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369(6483):756–758PubMedGoogle Scholar
  17. 17.
    Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78(1):35–43PubMedGoogle Scholar
  18. 18.
    Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270(2):815–822PubMedGoogle Scholar
  19. 19.
    Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168PubMedGoogle Scholar
  20. 20.
    Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137(5):873–886PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11(4):895–904PubMedGoogle Scholar
  22. 22.
    Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N (2010) Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 285(26):20109–20116PubMedCentralPubMedGoogle Scholar
  23. 23.
    Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ, Lee KW, Kim BY, Erikson RL, Cantley LC, Choo AY, Blenis J (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 49(1):172–185PubMedCentralPubMedGoogle Scholar
  24. 24.
    Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871PubMedGoogle Scholar
  25. 25.
    Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175PubMedGoogle Scholar
  26. 26.
    Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189PubMedGoogle Scholar
  27. 27.
    Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P, Arrieumerlou C, Hall MN (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2(11):e1217PubMedCentralPubMedGoogle Scholar
  28. 28.
    Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25(6):903–915PubMedGoogle Scholar
  29. 29.
    Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128PubMedGoogle Scholar
  30. 30.
    Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302PubMedGoogle Scholar
  31. 31.
    Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20(20):2820–2832PubMedCentralPubMedGoogle Scholar
  32. 32.
    Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137PubMedGoogle Scholar
  33. 33.
    Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16(18):1865–1870PubMedGoogle Scholar
  34. 34.
    Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405(3):513–522PubMedCentralPubMedGoogle Scholar
  35. 35.
    Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282(35):25604–25612PubMedGoogle Scholar
  36. 36.
    Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9(3):316–323PubMedGoogle Scholar
  37. 37.
    Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501PubMedCentralPubMedGoogle Scholar
  38. 38.
    Dunlop EA, Dodd KM, Seymour LA, Tee AR (2009) Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cell Signal 21(7):1073–1084PubMedGoogle Scholar
  39. 39.
    Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13(15):1259–1268PubMedGoogle Scholar
  40. 40.
    Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47(4):535–546PubMedCentralPubMedGoogle Scholar
  41. 41.
    Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17(15):1829–1834PubMedCentralPubMedGoogle Scholar
  42. 42.
    Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4(9):648–657PubMedGoogle Scholar
  43. 43.
    Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10(1):151–162PubMedGoogle Scholar
  44. 44.
    Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37(Pt 1):217–222PubMedCentralPubMedGoogle Scholar
  45. 45.
    Dibble CC, Asara JM, Manning BD (2009) Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 29(21):5657–5670PubMedCentralPubMedGoogle Scholar
  46. 46.
    Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332(6035):1317–1322PubMedCentralPubMedGoogle Scholar
  47. 47.
    Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121(2):179–193PubMedGoogle Scholar
  48. 48.
    Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282(19):14056–14064PubMedCentralPubMedGoogle Scholar
  49. 49.
    Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262PubMedGoogle Scholar
  50. 50.
    Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101(10):3329–3335PubMedCentralPubMedGoogle Scholar
  51. 51.
    Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590PubMedGoogle Scholar
  52. 52.
    Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226PubMedCentralPubMedGoogle Scholar
  53. 53.
    Hardie DG (2008) AMPK and Raptor: matching cell growth to energy supply. Mol Cell 30(3):263–265PubMedGoogle Scholar
  54. 54.
    Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955–968PubMedGoogle Scholar
  55. 55.
    Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534PubMedCentralPubMedGoogle Scholar
  56. 56.
    Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280(19):18717–18727PubMedGoogle Scholar
  57. 57.
    Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10(8):935–945PubMedCentralPubMedGoogle Scholar
  58. 58.
    Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290–303PubMedCentralPubMedGoogle Scholar
  59. 59.
    Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334(6056):678–683PubMedCentralPubMedGoogle Scholar
  60. 60.
    Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S (2012) Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149(2):410–424PubMedGoogle Scholar
  61. 61.
    Jewell JL, Guan KL (2013) Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38(5):233–242PubMedCentralPubMedGoogle Scholar
  62. 62.
    Kim SG, Buel GR, Blenis J (2013) Nutrient regulation of the mTOR Complex 1 signaling pathway. Mol Cells 35(6):463–473PubMedGoogle Scholar
  63. 63.
    Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18(23):2893–2904PubMedCentralPubMedGoogle Scholar
  64. 64.
    Sofer A, Lei K, Johannessen CM, Ellisen LW (2005) Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 25(14):5834–5845PubMedCentralPubMedGoogle Scholar
  65. 65.
    DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (2008) Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 22(2):239–251PubMedCentralPubMedGoogle Scholar
  66. 66.
    Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451–460PubMedCentralPubMedGoogle Scholar
  67. 67.
    Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102(23):8204–8209PubMedCentralPubMedGoogle Scholar
  68. 68.
    Lee DF, Hung MC (2007) All roads lead to mTOR: integrating inflammation and tumor angiogenesis. Cell Cycle 6(24):3011–3014PubMedGoogle Scholar
  69. 69.
    Foster DA (2009) Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim Biophys Acta 1791(9):949–955PubMedCentralPubMedGoogle Scholar
  70. 70.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293PubMedCentralPubMedGoogle Scholar
  71. 71.
    Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318PubMedGoogle Scholar
  72. 72.
    Mayer C, Zhao J, Yuan X, Grummt I (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18(4):423–434PubMedCentralPubMedGoogle Scholar
  73. 73.
    Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ (2010) mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci U S A 107(26):11823–11828PubMedCentralPubMedGoogle Scholar
  74. 74.
    Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8(3):224–236PubMedCentralPubMedGoogle Scholar
  75. 75.
    Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39(2):171–183PubMedCentralPubMedGoogle Scholar
  76. 76.
    Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146(3):408–420PubMedCentralPubMedGoogle Scholar
  77. 77.
    Kim JE, Chen J (2004) Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53(11):2748–2756PubMedGoogle Scholar
  78. 78.
    Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19(22):R1046–R1052PubMedCentralPubMedGoogle Scholar
  79. 79.
    Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS, Finkel T (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281(37):27643–27652PubMedGoogle Scholar
  80. 80.
    Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1[agr] transcriptional complex. Nature 450(7170):736–740PubMedGoogle Scholar
  81. 81.
    Ramanathan A, Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A 106(52):22229–22232PubMedCentralPubMedGoogle Scholar
  82. 82.
    Ganley IG, Lam DH, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284(18):12297–12305PubMedCentralPubMedGoogle Scholar
  83. 83.
    Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584(7):1287–1295PubMedCentralPubMedGoogle Scholar
  84. 84.
    Koren I, Reem E, Kimchi A (2010) DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 20(12):1093–1098PubMedGoogle Scholar
  85. 85.
    Koren I, Reem E, Kimchi A (2010) Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process. Autophagy 6(8):1179–1180PubMedCentralPubMedGoogle Scholar
  86. 86.
    Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10(14):2305–2316PubMedCentralPubMedGoogle Scholar
  87. 87.
    García-Martínez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416(3):375–385PubMedGoogle Scholar
  88. 88.
    Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144(5):757–768PubMedGoogle Scholar
  89. 89.
    Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28(12):4104–4115PubMedCentralPubMedGoogle Scholar
  90. 90.
    Copp J, Manning G, Hunter T (2009) TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69(5):1821–1827PubMedCentralPubMedGoogle Scholar
  91. 91.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101PubMedGoogle Scholar
  92. 92.
    Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Rüegg MA, Hall MN (2012) Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 15(5):725–738PubMedGoogle Scholar
  93. 93.
    Yuan M, Pino E, Wu L, Kacergis M, Soukas AA (2012) Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J Biol Chem 287(35):29579–29588PubMedCentralPubMedGoogle Scholar
  94. 94.
    Lamming DW, Sabatini DM (2013) A Central role for mTOR in lipid homeostasis. Cell Metab 18(4):465–469PubMedGoogle Scholar
  95. 95.
    Blagosklonny MV (2011) Cell cycle arrest is not senescence. Aging (Albany NY) 3(2):94–101Google Scholar
  96. 96.
    Foster DA, Yellen P, Xu L, Saqcena M (2010) Regulation of G1 cell cycle progression: distinguishing the restriction point from a nutrient-sensing cell growth checkpoint(s). Genes Cancer 1(11):1123–1131Google Scholar
  97. 97.
    Saqcena M, Menon D, Patel D, Mukhopadhyay S, Chow V, Foster DA (2013) Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle. PLoS One 8(8):e74157PubMedCentralPubMedGoogle Scholar
  98. 98.
    Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24(1):200–216PubMedCentralPubMedGoogle Scholar
  99. 99.
    Averous J, Fonseca BD, Proud CG (2008) Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27(8):1106–1113PubMedGoogle Scholar
  100. 100.
    Balcazar N, Sathyamurthy A, Elghazi L, Gould A, Weiss A, Shiojima I, Walsh K, Bernal-Mizrachi E (2009) mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J Biol Chem 284(12):7832–7842PubMedCentralPubMedGoogle Scholar
  101. 101.
    Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, Kozma SC, Thomas G, Sonenberg N (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328(5982):1172–1176PubMedCentralPubMedGoogle Scholar
  102. 102.
    Hong F, Larrea MD, Doughty C, Kwiatkowski DJ, Squillace R, Slingerland JM (2008) mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell 30(6):701–711PubMedGoogle Scholar
  103. 103.
    Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404(6779):782–787PubMedGoogle Scholar
  104. 104.
    Vadlakonda L, Pasupuleti M, Pallu R (2013) Role of PI3K-AKT-mTOR and Wnt Signaling Pathways in Transition of G1-S Phase of Cell Cycle in Cancer Cells. Front Oncol 3:85Google Scholar
  105. 105.
    Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ (2007) 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 67(7):3043–3053PubMedGoogle Scholar
  106. 106.
    Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20(3):267–275PubMedGoogle Scholar
  107. 107.
    Lee CH, Inoki K, Karbowniczek M, Petroulakis E, Sonenberg N, Henske EP, Guan KL (2007) Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 26(23):4812–4823PubMedCentralPubMedGoogle Scholar
  108. 108.
    Brenman JE (2007) AMPK/LKB1 signaling in epithelial cell polarity and cell division. Cell Cycle 6(22):2755–2759PubMedGoogle Scholar
  109. 109.
    Koh H, Chung J (2007) AMPK links energy status to cell structure and mitosis. Biochem Biophys Res Commun 362(4):789–792PubMedGoogle Scholar
  110. 110.
    Williams T, Brenman JE (2008) LKB1 and AMPK in cell polarity and division. Trends Cell Biol 18(4):193–198PubMedGoogle Scholar
  111. 111.
    Bettencourt-Dias M, Giet R, Sinka R, Mazumdar A, Lock WG, Balloux F, Zafiropoulos PJ, Yamaguchi S, Winter S, Carthew RW, Cooper M, Jones D, Frenz L, Glover DM (2004) Genome-wide survey of protein kinases required for cell cycle progression. Nature 432(7020):980–987PubMedGoogle Scholar
  112. 112.
    Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J (2007) Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447(7147):1017–1020PubMedGoogle Scholar
  113. 113.
    Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA (2009) Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells. Cell Cycle 8(10):1633–1636PubMedGoogle Scholar
  114. 114.
    Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Menendez JA (2009) AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor. Cell Cycle 8(22):3679–3683PubMedGoogle Scholar
  115. 115.
    Vazquez-Martin A, López-Bonet E, Oliveras-Ferraros C, Pérez-Martínez MC, Bernadó L, Menendez JA (2009) Mitotic kinase dynamics of the active form of AMPK (phospho-AMPKalphaThr172) in human cancer cells. Cell Cycle 8(5):788–791PubMedGoogle Scholar
  116. 116.
    Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) The active form of the metabolic sensor: AMP-activated protein kinase (AMPK) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis. Cell Cycle 8(15):2385–2398PubMedGoogle Scholar
  117. 117.
    Pinter K, Jefferson A, Czibik G, Watkins H, Redwood C (2012) Subunit composition of AMPK trimers present in the cytokinetic apparatus: implications for drug target identification. Cell Cycle 11(5):917–921PubMedGoogle Scholar
  118. 118.
    Menendez JA, Vazquez-Martin A (2012) AMPK: a bona fide resident of the mitotic spindle midzone. Cell Cycle 11(5):841–842PubMedGoogle Scholar
  119. 119.
    Banko MR, Allen JJ, Schaffer BE, Wilker EW, Tsou P, White JL, Villén J, Wang B, Kim SR, Sakamoto K, Gygi SP, Cantley LC, Yaffe MB, Shokat KM, Brunet A (2011) Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis. Mol Cell 44(6):878–892PubMedCentralPubMedGoogle Scholar
  120. 120.
    Robitaille AM, Hall MN (2012) Ramping up mitosis: an AMPKα2-regulated signaling network promotes mitotic progression. Mol Cell 45(1):8–9PubMedGoogle Scholar
  121. 121.
    Thaiparambil JT, Eggers CM, Marcus AI (2012) AMPK regulates mitotic spindle orientation through phosphorylation of myosin regulatory light chain. Mol Cell Biol 32(16):3203–3217PubMedCentralPubMedGoogle Scholar
  122. 122.
    Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Menendez JA (2012) Polo-like kinase 1 directs the AMPK-mediated activation of myosin regulatory light chain at the cytokinetic cleavage furrow independently of energy balance. Cell Cycle 11(13):2422–2426PubMedGoogle Scholar
  123. 123.
    Rafalski VA, Mancini E, Brunet A (2012) Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J Cell Sci 125(Pt23):5597–5608PubMedCentralPubMedGoogle Scholar
  124. 124.
    Mao L, Li N, Guo Y, Xu X, Gao L, Xu Y, Zhou L, Liu W (2013) AMPK phosphorylates GBF1 for mitotic Golgi disassembly. J Cell Sci 126(Pt 6):1498–1505PubMedGoogle Scholar
  125. 125.
    Vazquez-Martin A, Corominas-Faja B, Oliveras-Ferraros C, Cufí S, Dalla Venezia N, Menendez JA (2013) Serine79-phosphorylated acetyl-CoA carboxylase, a downstream target of AMPK, localizes to the mitotic spindle poles and the cytokinesis furrow. Cell Cycle 12(10):1639–1641PubMedCentralPubMedGoogle Scholar
  126. 126.
    Ito N, Rubin GM (1999) gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96(4):529–539PubMedGoogle Scholar
  127. 127.
    Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105(3):345–355PubMedGoogle Scholar
  128. 128.
    Catania MG, Mischel PS, Vinters HV (2001) Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. J Neuropathol Exp Neurol 60(7):711–723PubMedGoogle Scholar
  129. 129.
    Astrinidis A, Senapedis W, Coleman TR, Henske EP (2003) Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J Biol Chem 278(51):51372–51379PubMedGoogle Scholar
  130. 130.
    Astrinidis A, Senapedis W, Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet 15(2):287–297PubMedGoogle Scholar
  131. 131.
    Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Wetzel W, Schulze-Osthoff K, Nürnberg B, Piekorz RP (2007) The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. J Biol Chem 282(40):29273–29283PubMedGoogle Scholar
  132. 132.
    Gómez-Baldó L, Schmidt S, Maxwell CA, Bonifaci N, Gabaldón T, Vidalain PO, Senapedis W, Kletke A, Rosing M, Barnekow A, Rottapel R, Capellá G, Vidal M, Astrinidis A, Piekorz RP, Pujana MA (2010) TACC3-TSC2 maintains nuclear envelope structure and controls cell division. Cell Cycle 9(6):1143–1155PubMedGoogle Scholar
  133. 133.
    Ramírez-Valle F, Badura ML, Braunstein S, Narasimhan M, Schneider RJ (2010) Mitotic raptor promotes mTORC1 activity, G(2)/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation. Mol Cell Biol 30(13):3151–3164PubMedCentralPubMedGoogle Scholar
  134. 134.
    Gwinn DM, Asara JM, Shaw RJ (2010) Raptor is phosphorylated by cdc2 during mitosis. PLoS One 5(2):e9197PubMedCentralPubMedGoogle Scholar
  135. 135.
    Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Menendez JA (2011) Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs). Cell Cycle 10(18):3140–3152PubMedGoogle Scholar
  136. 136.
    Bachmann RA, Kim JH, Wu AL, Park IH, Chen J (2006) A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem 281(11):7357–7363PubMedGoogle Scholar
  137. 137.
    Vazquez-Martin A, Oliveras-Ferraros C, Bernadó L, López-Bonet E, Menendez JA (2009) The serine 2481-autophosphorylated form of mammalian Target Of Rapamycin (mTOR) is localized to midzone and midbody in dividing cancer cells. Biochem Biophys Res Commun 380(3):638–643PubMedGoogle Scholar
  138. 138.
    Lopez-Bonet E, Vazquez-Martin A, Pérez-Martínez MC, Oliveras-Ferraros C, Pérez-Bueno F, Bernadó L, Menendez JA (2010) Serine 2481-autophosphorylation of mammalian target of rapamycin (mTOR) couples with chromosome condensation and segregation during mitosis: confocal microscopy characterization and immunohistochemical validation of PP-mTOR(Ser2481) as a novel high-contrast mitosis marker in breast cancer core biopsies. Int J Oncol 36(1):107–115PubMedGoogle Scholar
  139. 139.
    Vazquez-Martin A, Sauri-Nadal T, Menendez OJ, Oliveras-Ferraros C, Cufí S, Corominas-Faja B, López-Bonet E, Menendez JA (2012) Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis. Cell Cycle 11(22):4211–4221PubMedCentralPubMedGoogle Scholar
  140. 140.
    Yaba A, Bianchi V, Borini A, Johnson J (2008) A putative mitotic checkpoint dependent on mTOR function control cell proliferation and survival in ovarian granulosa cells. Reprod Sci 15(2):128–138PubMedGoogle Scholar
  141. 141.
    Yu J, Yaba A, Kasiman C, Thomson T, Johnson J (2011) mTOR controls ovarian follicle growth by regulating granulosa cell proliferation. PLoS One 6(7):e21415PubMedCentralPubMedGoogle Scholar
  142. 142.
    Heesom KJ, Gampel A, Mellor H, Denton RM (2001) Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1). Curr Biol 11(17):1374–1379PubMedGoogle Scholar
  143. 143.
    Boyer D, Quintanilla R, Lee-Fruman KK (2008) Regulation of catalytic activity of S6 kinase 2 during cell cycle. Mol Cell Biochem 307(1–2):59–64PubMedCentralPubMedGoogle Scholar
  144. 144.
    Shah OJ, Ghosh S, Hunter T (2003) Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr, Pro phosphorylation of consensus and non-consensus sites by Cdc2. J Biol Chem 278(18):16433–16442PubMedGoogle Scholar
  145. 145.
    Schmidt T, Wahl P, Wüthrich RP, Vogetseder A, Picard N, Kaissling B, Le Hir M (2007) Immunolocalization of phospho-S6 kinases: a new way to detect mitosis in tissue sections and in cell culture. Histochem Cell Biol 127(2):123–129PubMedCentralPubMedGoogle Scholar
  146. 146.
    Park IH, Bachmann R, Shirazi H, Chen J (2002) Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem 277(35):31423–31429PubMedGoogle Scholar
  147. 147.
    Filonenko VV, Tytarenko R, Azatjan SK, Savinska LO, Gaydar YA, Gout IT, Usenko VS, Lyzogubov VV (2004) Immuno-histochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol 26(4):294–299Google Scholar
  148. 148.
    Rossi R, Pester JM, McDowell M, Soza S, Montecucco A, Lee-Fruman KK (2007) Identification of S6K2 as a centrosome-located kinase. FEBS Lett 581(21):4058–4064PubMedCentralPubMedGoogle Scholar
  149. 149.
    Fingar DC, Salama S, Tsou C, Harlow E, Blenis J (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16(12):1472–1487PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Elisabet Cuyàs
    • 1
  • Bruna Corominas-Faja
    • 1
  • Jorge Joven
    • 2
  • Javier A. Menendez
    • 1
  1. 1.Metabolism & Cancer Group, Translational Research LaboratoryCatalan Institute of Oncology, Girona (ICO-Girona), Hospital Dr. Josep Trueta de GironaGironaSpain
  2. 2.Unitat de Recerca Biomèdica (URB-CRB)Institut d’Investigació Sanitaria Pere i Virgili (IISPV), Universitat Rovira i VirgiliReusSpain

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