Abstract
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is required for normal development, growth, and physiology. Mutations in multiple key regulators of this pathway have been reported to occur leading to aberrant signaling and have been implicated in a number of pathologies, including metabolic syndrome. This chapter will review the major proteins involved in PI3K/mTOR signaling and discuss the negative feedback loops which maintain homeostasis. The therapeutic advantages and limitations of PI3K and/or catalytic mTOR inhibitors, which are currently in clinical development, will be discussed. We also report studies using these inhibitors along with genetic models to delete or overexpress key players in PI3K/mTOR signaling pathways in yeast, worms, drosophila, and mice, which have been instrumental in elucidating the functions of these proteins in normal and disease states. Particular attention has been focused on the role of PI3K/mTOR signaling in proliferation, translation, metabolism (including energy balance regulation and metabolic syndrome), autophagy, and differentiation.
$Author contributed equally with all other contributors.
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References
Long X, et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol. 2002;12(17):1448–61.
Oldham S, et al. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 2000;14(21):2689–94.
Zhang H, et al. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 2000;14(21):2712–24.
Gangloff YG, et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol. 2004;24(21):9508–16.
Murakami M, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol. 2004;24(15):6710–8.
Matsuo T, et al. Schizosaccharomyces pombe AGC family kinase Gad8p forms a conserved signaling module with TOR and PDK1-like kinases. EMBO J. 2003;22(12):3073–83.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.
Peterson TR, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.
Kaizuka T, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem. 2010;285(26):20109–16.
Kim DH, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895–904.
Hara K, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89.
Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol. 2002;12(8):632–9.
Sancak Y, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.
Wang L, et al. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282(27):20036–44.
Hsu PP, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317–22.
Yu Y, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332(6035):1322–6.
Lamming DW, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335(6076):1638–43.
Thomas HE, et al. mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med. 2012;4(139):139ra84.
Jacinto E, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8.
Loewith R, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457–68.
Sarbassov DD, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101.
Jacinto E, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125–37.
Frias MA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16(18):1865–70.
Pearce LR, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J. 2007;405(3):513–22.
Pearce LR, et al. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J. 2011;436(1):169–79.
Thedieck K, et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One. 2007;2(11):e1217.
Sarbassov DD, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–302.
Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008;416(3):375–85.
Ikenoue T, et al. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008;27(14):1919–31.
Nobukuni T, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A. 2005;102(40):14238–43.
Vander Haar E, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007;9(3):316–23.
Garami A, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 2003;11(6):1457–66.
Long X, et al. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005;15(8):702–13.
Haas DW, Hagedorn CH. Protein kinase C phosphorylates both serine and threonine residues of the mRNA cap binding protein eIF-4E. Second Messengers Phosphoproteins. 1992;14(1–2):55–63.
Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8(5):387–98.
Inoki K, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126(5):955–68.
Lee DF, et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell. 2007;130(3):440–55.
Brugarolas J, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004;18(23):2893–904.
DeYoung MP, et al. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22(2):239–51.
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(23):2879–92.
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577–90.
Shaw RJ, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91–9.
Kalender A, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401.
Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26.
Chantranupong L, et al. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 2014;9(1):1–8.
Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134(3):451–60.
Feng Z, et al. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A. 2005;102(23):8204–9.
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(38):33076–82.
Kim E, et al. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008;10(8):935–45.
Sancak Y, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320(5882):1496–501.
Efeyan A, et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature. 2013;493(7434):679–83.
Sancak Y, et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290–303.
Bar-Peled L, et al. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012;150(6):1196–208.
Tsun ZY, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495–505.
Menon S, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156(4):771–85.
Zoncu R, et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678–83.
Bar-Peled L, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100–6.
Panchaud N, Peli-Gulli MP, De Virgilio C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal. 2013;6(277):ra42.
Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.
Zinzalla V, et al. Activation of mTORC2 by association with the ribosome. Cell. 2011;144(5):757–68.
Huang J, et al. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol. 2008;28(12):4104–15.
Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. 2009;37(Pt 1):217–22.
Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412(2):179–90.
Yang Q, et al. TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci U S A. 2006;103(18):6811–6.
Goncharova EA, et al. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol. 2011;31(12):2484–98.
Kamimura Y, et al. PIP3-independent activation of TorC2 and PKB at the cell’s leading edge mediates chemotaxis. Curr Biol. 2008;18(14):1034–43.
Charest PG, et al. A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Dev Cell. 2010;18(5):737–49.
Cai H, et al. Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis. J Cell Biol. 2010;190(2):233–45.
Dalle Pezze P, et al. A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal. 2012;5(217):ra25.
Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010;22(2):169–76.
Radimerski T, et al. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 2002;16(20):2627–32.
Radimerski T, et al. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat Cell Biol. 2002;4(3):251–5.
Jaeschke A, et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol. 2002;159(2):217–24.
Harrington LS, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166(2):213–23.
Hartley D, Cooper GM. Role of mTOR in the degradation of IRS-1: regulation of PP2A activity. J Cell Biochem. 2002;85(2):304–14.
Haruta T, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol. 2000;14(6):783–94.
Takano A, et al. 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(15):5050–62.
Carracedo A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74.
Zhang H, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007;117(3):730–8.
Gupta S, et al. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell. 2007;129(5):957–68.
Ma L, et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179–93.
Wells V, Downward J, Mallucci L. Functional inhibition of PI3K by the betaGBP molecule suppresses Ras-MAPK signalling to block cell proliferation. Oncogene. 2007;26(55):7709–14.
Wennstrom S, Downward J. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Mol Cell Biol. 1999;19(6):4279–88.
Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009;29(21):5657–70.
Vasudevan KM, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16(1):21–32.
Sarbassov DD, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.
Um SH, D’Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab. 2006;3(6):393–402.
Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.
Thoreen CC, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023–32.
O'Reilly KE, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500–8.
Cloughesy TF, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008;5(1):e8.
Meric-Bernstam F, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18(6):1777–89.
Choo AY, et al. 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(45):17414–9.
Maira SM, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7(7):1851–63.
Benjamin D, et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011;10(11):868–80.
Bendell JC, et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs. 2015;33(2):463–71.
Britten CD, et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest New Drugs. 2014;32(3):510–7.
Markman B, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012;23(9):2399–408.
Shapiro GI, et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res. 2015;21(8):1888–95.
Mahadevan D, et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer. 2012;48(18):3319–27.
Nyfeler B, et al. RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth. PLoS One. 2012;7(11):e48548.
Mazzoletti M, et al. Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res. 2011;71(13):4573–84.
Werzowa J, et al. Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo. J Invest Dermatol. 2011;131(2):495–503.
Xu CX, et al. The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo. PLoS One. 2011;6(6):e20899.
Liu Q, et al. Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. J Biol Chem. 2012;287(13):9742–52.
Duncan JS, Haystead TA, Litchfield DW. Chemoproteomic characterization of protein kinase inhibitors using immobilized ATP. Methods Mol Biol. 2012;795:119–34.
Kong D, Yaguchi S, Yamori T. Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase. Biol Pharm Bull. 2009;32(2):297–300.
Beuvink I, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. 2005;120(6):747–59.
Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol. 2013;10(4):191–210.
Miller BW, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21(7):1525–9.
Juric D, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature. 2015;518(7538):240–4.
Chakrabarty A, et al. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109(8):2718–23.
Zheng XF, et al. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell. 1995;82(1):121–30.
Barbet NC, et al. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996;7(1):25–42.
Guertin DA, et al. 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. 2006;11(6):859–71.
Shiota C, et al. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11(4):583–9.
Albers MW, et al. FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. J Biol Chem. 1993;268(30):22825–9.
Dowling RJ, et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science. 2010;328(5982):1172–6.
Montagne J, et al. Drosophila S6 kinase: a regulator of cell size. Science. 1999;285(5436):2126–9.
Espeillac C, et al. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. J Clin Invest. 2011;121(7):2821–32.
Gu Y, et al. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes. 2011;60(3):827–37.
Zhu Y, et al. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One. 2013;8(1):e54221.
Gentilella A, Kozma SC, Thomas G. A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochim Biophys Acta. 2015;1849(7):812–20.
Mathews M, Hershey JWB, Sonenberg N. Translational control in biology and medicine. 3rd ed. Cold Spring Harbor monograph series;. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2007. 934 p.
Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136(4):731–45.
Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11(2):113–27.
van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10(4):301–9.
Ruggero D, et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med. 2004;10(5):484–6.
Rosen N, She QB. AKT and cancer–is it all mTOR? Cancer Cell. 2006;10(4):254–6.
Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway–beyond rapalogs. Oncotarget. 2010;1(7):530–43.
Hsieh AC, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485(7396):55–61.
Buttgereit F, Brand MD. A hierarchy of ATP-consuming processes in mammalian cells. Biochem J. 1995;312(Pt 1):163–7.
Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev. 1997;77(3):731–58.
Morita M, et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 2013;18(5):698–711.
Cunningham JT, et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450(7170):736–40.
Gingras AC, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 2001;15(21):2852–64.
Gingras AC, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999;13(11):1422–37.
Gygi SP, et al. Protein analysis by mass spectrometry and sequence database searching: tools for cancer research in the post-genomic era. Electrophoresis. 1999;20(2):310–9.
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.
Levy S, et al. Oligopyrimidine tract at the 5′ end of mammalian ribosomal protein mRNAs is required for their translational control. Proc Natl Acad Sci U S A. 1991;88(8):3319–23.
Jefferies HB, et al. Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc Natl Acad Sci U S A. 1994;91(10):4441–5.
Jefferies HB, et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997;16(12):3693–704.
Thoreen CC, et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012;485(7396):109–13.
Aoki K, et al. LARP1 specifically recognizes the 3′ terminus of poly(A) mRNA. FEBS Lett. 2013;587(14):2173–8.
Tcherkezian J, et al. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation. Genes Dev. 2014;28(4):357–71.
Pyronnet S, et al. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. EMBO J. 1999;18(1):270–9.
Grzmil M, et al. MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. J Clin Invest. 2014;124(2):742–54.
Pardo OE, Seckl MJ. S6K2: the neglected S6 kinase family member. Front Oncol. 2013;3:191.
Holz MK, et al. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123(4):569–80.
Dorrello NV, et al. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314(5798):467–71.
Wang X, et al. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20(16):4370–9.
Ben-Sahra I, et al. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science. 2013;339(6125):1323–8.
Robitaille AM, et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science. 2013;339(6125):1320–3.
Lane AN, Fan TW. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 2015;43(4):2466–85.
Mayer C, et al. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 2004;18(4):423–34.
Liwak U, et al. Tumor suppressor PDCD4 represses internal ribosome entry site-mediated translation of antiapoptotic proteins and is regulated by S6 kinase 2. Mol Cell Biol. 2012;32(10):1818–29.
Brugarolas JB, et al. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003;4(2):147–58.
Duvel K, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39(2):171–83.
Hudson CC, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004–14.
Laughner E, et al. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21(12):3995–4004.
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763–77.
Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol. 2009;19(22):R1046–52.
Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A. 2010;107(8):3441–6.
Porstmann T, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224–36.
Wang BT, et al. The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. Proc Natl Acad Sci U S A. 2011;108(37):15201–6.
Peterson TR, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146(3):408–20.
Kim JE, Chen J. regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes. 2004;53(11):2748–56.
Zhang HH, et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS One. 2009;4(7):e6189.
Carnevalli LS, et al. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell. 2010;18(5):763–74.
Le Bacquer O, et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest. 2007;117(2):387–96.
Polak P, et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 2008;8(5):399–410.
Um SH, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431(7005):200–5.
Cybulski N, et al. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci U S A. 2009;106(24):9902–7.
Kumar A, et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes. 2010;59(6):1397–406.
Yao Y, et al. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci Signal. 2013;6(257):ra2.
Hung CM, et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 2014;8(1):256–71.
Philp A, Hamilton DL, Baar K. Signals mediating skeletal muscle remodeling by resistance exercise: PI3-kinase independent activation of mTORC1. J Appl Physiol (1985).,2011;110(2):561–8.
Bentzinger CF, et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 2008;8(5):411–24.
Cota D, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312(5775):927–30.
Cota D, et al. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci. 2008;28(28):7202–8.
Blouet C, Ono H, Schwartz GJ. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab. 2008;8(6):459–67.
Sengupta S, et al. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010;468(7327):1100–4.
Kim K, Pyo S, Um SH. S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver. Hepatology. 2012;55(6):1727–37.
Tremblay F, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2007;104(35):14056–61.
Khamzina L, et al. 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(3):1473–81.
Rachdi L, 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 U S A. 2008;105(27):9250–5.
Shigeyama Y, et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol. 2008;28(9):2971–9.
Pende M, et al. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature. 2000;408(6815):994–7.
Elghazi L, et al. Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells. Diabetes. 2010;59(10):2390–9.
Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7(2):95–6.
Bae EJ, et al. Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance. J Biol Chem. 2012;287(22):18769–80.
Stallone G, et al. Management of side effects of sirolimus therapy. Transplantation. 2009;87(8 Suppl):S23–6.
Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the underlying molecular mechanisms. Diabetes. 2013;62(8):2674–82.
Shang L, et al. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108(12):4788–93.
Kim J, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–41.
Nazio F, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013;15(4):406–16.
Egan DF, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331(6016):456–61.
Martina JA, et al. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8(6):903–14.
Kuma A, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6.
Komatsu M, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169(3):425–34.
Sou YS, et al. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell. 2008;19(11):4762–75.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.
Laderoute KR, et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol. 2006;26(14):5336–47.
Koren I, Reem E, Kimchi A. DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol. 2010;20(12):1093–8.
Fan QW, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal. 2010;3(147):ra81.
Song YJ, et al. Autophagy contributes to the survival of CD133+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Lett. 2013;339(1):70–81.
Bray K, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One. 2012;7(7):e41831.
Yang Z, et al. Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations. PLoS One. 2011;6(12):e28405.
Fang DD, et al. Antitumor efficacy of the dual PI3K/mTOR inhibitor PF-04691502 in a human xenograft tumor model derived from colorectal cancer stem cells harboring a mutation. PLoS One. 2013;8(6):e67258.
Dubrovska A, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A. 2009;106(1):268–73.
Kolev VN, et al. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015;75(2):446–55.
Sunayama J, et al. Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells. Neuro Oncol. 2010;12(12):1205–19.
Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13(6):252–9.
Sampath P, et al. A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell. 2008;2(5):448–60.
Santos AC, Lehmann R. Germ cell specification and migration in Drosophila and beyond. Curr Biol. 2004;14(14):R578–89.
Strome S, Lehmann R. Germ versus soma decisions: lessons from flies and worms. Science. 2007;316(5823):392–3.
Easley CA, et al. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram. 2010;12(3):263–73.
Castilho RM, et al. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009;5(3):279–89.
Faller WJ, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015;517(7535):497–500.
Agrawal P, et al. DEPTOR is a stemness factor that regulates pluripotency of embryonic stem cells. J Biol Chem. 2014;289(46):31818–26.
Sunayama J, et al. Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells. Stem Cells. 2010;28(11):1930–9.
Zhou J, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007;104(41):16158–63.
Matsumoto K, et al. mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res. 2009;69(18):7160–4.
Yang Z, et al. Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations. PLoS One. 2011;6(12):e28405.
LaFever L, et al. Specific roles of target of rapamycin in the control of stem cells and their progeny in the Drosophila ovary. Development. 2010;137(13):2117–26.
Sun P, et al. TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation. Development. 2010;137(15):2461–9.
Amcheslavsky A, Jiang J, Ip YT. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell. 2009;4(1):49–61.
Biteau B, Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development. 2011;138(6):1045–55.
Chell JM, Brand AH. Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell. 2010;143(7):1161–73.
Sousa-Nunes R, Yee LL, Gould AP. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature. 2011;471(7339):508–12.
Martin SK, et al. The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells. 2014;33(4):1359–65.
Bercury KK, et al. Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J Neurosci. 2014;34(13):4466–80.
Acknowledgments
We are thankful to G. Doerman for the assistance with preparation of figures. H.E.T is supported by a faculty pilot project grant by the Department of Internal Medicine, University of Cincinnati, OH. G.T. is supported by grants from the Instituto de Salud Carlos III (IIS10/00015), the Spanish Ministry of Science and Innovation (SAF2014-52162), the CIG European Commission (PCIG10-GA-2011-304160), and the NIH/NCI National Cancer Institute (R01-CA158768). S.C.K is supported by grants from the Instituto de Salud Carlos III (IIS12/00002) GT and SCK are also supported by the European Regional Development Fund FEDER in Spain and from the Spanish Ministry of Economy and Competitivity (BFU2012-38867).
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Thomas, H.E., da Veiga, S.R.P., Thomas, G., Kozma, S.C. (2016). The PI3K-mTOR Pathway. In: Mita, M., Mita, A., Rowinsky, E. (eds) mTOR Inhibition for Cancer Therapy: Past, Present and Future. Springer, Paris. https://doi.org/10.1007/978-2-8178-0492-7_2
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