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http://dx.doi.org/10.5483/BMBRep.2017.50.12.206

Upstream signalling of mTORC1 and its hyperactivation in type 2 diabetes (T2D)  

Ali, Muhammad (Department of Biochemistry, Government College University)
Bukhari, Shazia Anwer (Department of Biochemistry, Government College University)
Ali, Muhammad (Department of Zoology, Government College University)
Lee, Han-Woong (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
Publication Information
BMB Reports / v.50, no.12, 2017 , pp. 601-609 More about this Journal
Abstract
Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrientrich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.
Keywords
Diabetes; Hypertriglyceridemia; Insulin resistance; mTORC1 restriction;
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1 Kerner J and Hoppel C (2000) Fatty acid import into mitochondria. Biochim Biophys Acta 1486, 1-17   DOI
2 Nojima H, Tokunaga C, Eguchi S et al (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates, p70 S6 kinase and 4E-BP1, through their TOR signaling (TOS) motif. J Biol Chem 278, 15461-15464   DOI
3 Roberts DJ, Tan-Sah VP, Ding EY, Smith JM and Miyamoto S (2014) Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 53, 521-533   DOI
4 Feng Z, Zhang H, Levine AJ and Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102, 8204-8209   DOI
5 Bukhari SA, Javed S, Ali M, Shahzadi A and Rehman M (2015) Serum haematological and biochemical indices of oxidative stress and their relationship with DNA damage and homocysteine in Pakistani type II diabetic patients. Pak J Pharm Sci 28, 881-889
6 Association AD (2010) Diagnosis and classification of diabetes mellitus. Diabetes care 33, S62-S69   DOI
7 Billington CJ, Epstein LH, Goodwin NJ et al (2000) Overweight, obesity, and health risk. Arch Intern Med 160, 898-904   DOI
8 Volkers M, Doroudgar S, Nguyen N et al (2014) PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. Embo Mol Med 6, 57-65   DOI
9 Samuel VT and Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852-871   DOI
10 Han J, Li E, Chen L et al (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524, 243-246   DOI
11 Cornu M, Oppliger W, Albert V et al (2014) Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proc Natl Acad Sci U S A 111, 11592-11599   DOI
12 Chang L, Chiang S-H and Saltiel AR (2004) Insulin signaling and the regulation of glucose transport. Mol Med 10, 65-71
13 Engelman JA, Luo J and Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7, 606-619
14 Chalhoub N and Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4, 127-150   DOI
15 Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-205   DOI
16 Thedieck K, Holzwarth B, Prentzell MT et al (2013) Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell 154, 859-874   DOI
17 Melnik BC, John SM, Carrera-Bastos P and Cordain L (2012) The impact of cow's milk-mediated mTORC1- signaling in the initiation and progression of prostate cancer. Nutr Metab 9, 74   DOI
18 Uno K, Yamada T, Ishigaki Y et al (2015) A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals. Nat Commun 6, 7940   DOI
19 Tremblay F, Lavigne C, Jacques H and Marette A (2007) Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 27, 293-310   DOI
20 Zoncu R, Efeyan A and Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21-35   DOI
21 Passtoors WM, Beekman M, Deelen J et al (2013) Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell 12, 24-31   DOI
22 Laplante M and Sabatini DM (2010) mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci U S A 107, 3281-3282   DOI
23 Ginsberg HN (2000) Insulin resistance and cardiovascular disease. J Clin Invest 106, 453-458   DOI
24 Yecies JL, Zhang HH, Menon S et al (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14, 21-32   DOI
25 Kumashiro N, Beddow SA, Vatner DF et al (2013) Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 62, 2183-2194   DOI
26 Song SM, Andrikopoulos S, Filippis C, Thorburn AW, Khan D and Proietto J (2001) Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am J Physiol-Endoc M 281, E275-E282
27 Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS and Goldstein JL (2000) Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6, 77-86   DOI
28 Jin ES, Szuszkiewicz-Garcia M, Browning JD, Baxter JD, Abate N and Malloy CR (2015) Influence of liver triglycerides on suppression of glucose production by insulin in men. J Clin Endocr Metab 100, 235-243   DOI
29 Munoz P, Blanco R, Flores JM and Blasco MA (2005) XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat Genet 37, 1063-1071   DOI
30 Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocr Metab 87, 3023-3028   DOI
31 Steinert S, Shay JW and Wright WE (2004) Modification of subtelomeric DNA. Mol Cell Biol 24, 4571-4580   DOI
32 Ornish D, Lin J, Daubenmier J et al (2008) Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol 9, 1048-1057   DOI
33 Nettleton JA, Diez-Roux A, Jenny NS, Fitzpatrick AL and Jacobs DR (2008) Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 88, 1405-1412
34 Mirabello L, Huang WY, Wong JY et al (2009) The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer. Aging Cell 8, 405-413   DOI
35 Knoops KT, de Groot LC, Kromhout D et al (2004) Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 292, 1433-1439   DOI
36 von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27, 339-344   DOI
37 Rode L, Nordestgaard BG, Weischer M and Bojesen SE (2014) Increased body mass index, elevated C-reactive protein, and short telomere length. J Clin Endocrinol Metab 99, E1671-E1675   DOI
38 Dibble CC and Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15, 555-564   DOI
39 Floyd S, Favre C, Lasorsa FM et al (2007) The insulin-like growth Factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth. Mol Biol Cell 18, 3545-3555   DOI
40 Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, and Van Obberghen E (2004) Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J 18, 1894-1896   DOI
41 Inoki K, Li Y, Zhu TQ, Wu J and Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648-657   DOI
42 Inoki K, Li Y, Xu T and Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Gene Dev 17, 1829-1834   DOI
43 Catania C, Binder E and Cota D (2011) mTORC1 signaling in energy balance and metabolic disease. Int J Obes (Lond.) 35, 751-761   DOI
44 Guo N, Parry EM, Li L-S et al (2011) Short telomeres compromise ${\beta}$-cell signaling and survival. PLoS One 6, e17858   DOI
45 Jeanclos E, Krolewski A, Skurnick J et al (1998) Shortened telomere length in white blood cells of patients with IDDM. Diabetes 47, 482-486   DOI
46 Ma D, Zhu W, Hu S, Yu X and Yang Y (2013) Association between oxidative stress and telomere length in Type 1 and Type 2 diabetic patients. J Endocrinol Invest 36, 1032-1037
47 Geraldes P and King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106, 1319-1331   DOI
48 Minamino T, Orimo M, Shimizu I et al (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15, 1082-1087   DOI
49 Vander Heiden MG, Cantley LC and Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033   DOI
50 Nakashima RA, Paggi MG and Pedersen PL (1984) Contributions of glycolysis and oxidative phosphorylation to adenosine 5'-triphosphate production in AS-30D hepatoma cells. Cancer Res 44, 5702-5706
51 Bartlett K and Eaton S (2004) Mitochondrial ${\beta}$-oxidation. Eur J Biochem 271, 462-469   DOI
52 Sato R, Goldstein JL and Brown MS (1993) Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-coa reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc Natl Acad Sci U S A 90, 9261-9265   DOI
53 Houde VP, Brule S, Festuccia WT et al (2010) Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338-1348   DOI
54 Stallone G, Infante B, Grandaliano G and Gesualdo L (2009) Management of side effects of sirolimus therapy. Transplantation 87, S23-26   DOI
55 Cruzado JM (2008) Nonimmunosuppressive effects of mammalian target of rapamycin inhibitors. Transplant Rev 22, 73-81   DOI
56 Morrisett JD, Abdel-Fattah G, Hoogeveen R et al (2002) Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 43, 1170-1180
57 Um SH, D'Alessio D and Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3, 393-402   DOI
58 Zoncu R, Efeyan A and Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21-35   DOI
59 Ali M, Devkota S, Roh JI, Lee J and Lee HW (2016) Telomerase reverse transcriptase induces basal and amino acid starvation-induced autophagy through mTORC1. Biochem Biophys Res Commun 478, 1198-1204   DOI
60 Cheng H, Fan X, Lawson WE, Paueksakon P and Harris RC (2015) Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy. Kidney Int 88, 85-94   DOI
61 Taylor PM (2014) Role of amino acid transporters in amino acid sensing. Am J Clin Nutr 99, 223S-230S   DOI
62 Jewell JL, Russell RC and Guan K-L (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14, 133-139   DOI
63 Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC alpha but not S6K1. Dev Cell 11, 859-871   DOI
64 Fraenkel M, Ketzinel-Gilad M, Ariav Y et al (2008) mTOR inhibition by rapamycin prevents ${\beta}$-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57, 945-957   DOI
65 Sundin T, Peffley DM and Hentosh P (2013) Disruption of an hTERT-mTOR-RAPTOR protein complex by a phytochemical perillyl alcohol and rapamycin. Mol Cell Biochem 375, 97-104
66 Kawauchi K, Ihjima K and Yamada O (2005) IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol 174, 5261-5269   DOI
67 Berg CE, Lavan BE and Rondinone CM (2002) Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Biophy Res Commun 293, 1021-1027   DOI
68 Sahin E, Colla S, Liesa M et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359   DOI
69 Jia GH, Aroor AR, Martinez-Lemus LA and Sowers JR (2014) Overnutrition, mTOR signaling, and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 307, R1198-R1206   DOI
70 Greider CW (2016) Regulating telomere length from the inside out: the replication fork model. Gene Dev 30, 1483-1491   DOI
71 Kuhlow D, Florian S, von Figura G et al (2010) Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging (Albany NY) 2, 650
72 Lynch CJ (2001) Role of leucine in the regulation of mTOR by amino acids: Revelations from structure-activity studies. J Nutr 131, 861s-865s   DOI
73 Wrighton KH (2013) Cell signalling: Where the mTOR action is. Nat Rev Mol Cell Biol 14, 191   DOI
74 Schalm SS and Blenis J (2002) Identification of a conserved motif required for mTOR signaling. Curr Biol 12, 632-639   DOI
75 Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J and Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51, 283-296   DOI
76 Rosner M, Siegel N, Valli A, Fuchs C and Hengstschlager M (2010) mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids 38, 223-228   DOI
77 Kim E, Goraksha-Hicks P, Li L, Neufeld TP and Guan KL (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10, 935-945   DOI
78 Wolfson RL, Chantranupong L, Saxton RA et al (2016) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science (New York, N.Y.) 351, 43-48   DOI
79 Jewell JL, Kim YC, Russell RC et al (2015) Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194-198   DOI
80 Sancak Y, Peterson TR, Shaul YD et al (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501   DOI
81 Chantranupong L, Wolfson RL, Orozco JM et al (2014) The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep 9, 1-8   DOI
82 Parmigiani A, Nourbakhsh A, Ding B et al (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9, 1281-1291   DOI
83 Long X, Lin Y, Ortiz-Vega S, Yonezawa K and Avruch J (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15, 702-713   DOI
84 Shimobayashi M and Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15, 155-162   DOI
85 Peterson TR, Laplante M, Thoreen CC et al (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873-886   DOI
86 Sancak Y, Thoreen CC, Peterson TR et al (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25, 903-915   DOI
87 Ohji G, Hidayat S, Nakashima A et al (2006) Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin. J Biochem 139, 129-135   DOI
88 Dalle Pezze P, Sonntag AG, Thien A et al (2012) A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 5, ra25
89 Wang S, Tsun Z-Y, Wolfson RL et al (2015) Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188-194   DOI
90 Workman JJ, Chen HF and Laribee RN (2014) Environmental signaling through the mechanistic target of rapamycin complex 1 mTORC1 goes nuclear. Cell Cycle 13, 714-725   DOI
91 Cybulski N and Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends in Biochemical Sciences 34, 620-627   DOI
92 Kim DH, Sarbassov DD, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175   DOI
93 Laplante M and Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122, 3589-3594   DOI
94 Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J and Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51, 283-296   DOI
95 Duran A, Amanchy R, Linares JF et al (2011) p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 44, 134-146   DOI
96 Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149, 274-293   DOI
97 Avila-Flores A, Santos T, Rincon E and Merida I (2005) Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J Biol Chem 280, 10091-10099   DOI
98 Sengupta S, Peterson TR, Laplante M, Oh S and Sabatini DM (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100-1104   DOI
99 Inoki K, Zhu TQ and Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590   DOI
100 Gwinn DM, Shackelford DB, Egan DF et al (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214-226   DOI
101 Zielinski DC, Jamshidi N, Corbett AJ, Bordbar A, Thomas A and Palsson BO (2017) Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism. Sci Rep 7, 41241   DOI
102 Towler MC and Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100, 328-341   DOI
103 Kim J, Kundu M, Viollet B and Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141   DOI
104 Hardwick JP, Eckman K, Lee YK et al (2013) Eicosanoids in metabolic syndrome. Adv Pharmacol (San Diego, Calif.) 66, 157-266