Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

The Role of IL-6 Released During Exercise to Insulin Sensitivity and Muscle Hypertrophy

Author(s): Álvaro Nóbrega de Melo Madureira, João Ricardhis Saturnino de Oliveira and Vera Lúcia de Menezes Lima*

Volume 22, Issue 18, 2022

Published on: 18 April, 2022

Page: [2419 - 2428] Pages: 10

DOI: 10.2174/1389557522666220309161245

Price: $65

conference banner
Abstract

Interleukin-6 (IL-6) influences both inflammatory response and anti-inflammatory processes. This cytokine can be released by exercising skeletal muscle, which characterizes it as a myokine. Unlike what is observed in inflammation, IL-6 produced by skeletal muscle is not preceded by the release of other pro-inflammatory cytokines, but it seems to be dependent on the lactate produced during exercise, thus causing different effects from those seen in inflammatory state. After binding to its receptor, myokine IL-6 activates the PI3K-Akt pathway. One consequence of this upregulation is the potentiation of insulin signaling, which enhances insulin sensitivity. IL-6 increases GLUT-4 vesicle mobilization to the muscle cell periphery, increasing the glucose transport into the cell, and also glycogen synthesis. Muscle glycogen provides energy for ATP resynthesis, and regulates Ca2+ release by the sarcoplasmic reticulum, influencing muscle contraction, and, hence, muscle function by multiple pathways. Another implication for the upregulation of the PI3K-Akt pathway is the activation of mTORC1, which regulates mRNA translational efficiency by regulating translation machinery, and translational capacity by inducing ribosomal biogenesis. Thus, IL-6 may contribute to skeletal muscle hypertrophy and function by increasing contractile protein synthesis.

Keywords: Cytokine, diabetes, glucose, hypertrophy, TNF-α, glycogen.

« Previous
Graphical Abstract

[1]
Gabay, C. Interleukin-6 and chronic inflammation. Arthritis Res. Ther., 2006, 8(Suppl. 2), S3.
[2]
Neurath, M.F.; Finotto, S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev., 2011, 22(2), 83-89.
[http://dx.doi.org/10.1016/j.cytogfr.2011.02.003] [PMID: 21377916]
[3]
Jorgensen, S.B.; O’Neill, H.M.; Sylow, L.; Honeyman, J.; Hewitt, K.A.; Palanivel, R.; Fullerton, M.D.; Öberg, L.; Balendran, A.; Galic, S.; van der Poel, C.; Trounce, I.A.; Lynch, G.S.; Schertzer, J.D.; Steinberg, G.R. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes, 2013, 62(1), 56-64.
[http://dx.doi.org/10.2337/db12-0443] [PMID: 22961088]
[4]
Drenth, J.P.; Van Uum, S.H.; Van Deuren, M.; Pesman, G.J.; Van der Ven-Jongekrijg, J.; Van der Meer, J.W. Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production. J. Appl. Physiol., 1995, 79(5), 1497-1503.
[http://dx.doi.org/10.1152/jappl.1995.79.5.1497] [PMID: 8594005]
[5]
Pedersen, B.K.; Febbraio, M.A. Muscle as an endocrine organ: Focus on muscle-derived interleukin-6. Physiol. Rev., 2008, 88(4), 1379-1406.
[http://dx.doi.org/10.1152/physrev.90100.2007] [PMID: 18923185]
[6]
Bruunsgaard, H.; Galbo, H.; Halkjaer-Kristensen, J.; Johansen, T.L.; MacLean, D.A.; Pedersen, B.K. Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage. J. Physiol., 1997, 499(Pt 3), 833-841.
[http://dx.doi.org/10.1113/jphysiol.1997.sp021972] [PMID: 9130176]
[7]
Peake, J.M.; Suzuki, K.; Wilson, G.; Hordern, M.; Nosaka, K.; Mackinnon, L.; Coombes, J.S. Exercise-induced muscle damage, plasma cytokines, and markers of neutrophil activation. Med. Sci. Sports Exerc., 2005, 37(5), 737-745.
[http://dx.doi.org/10.1249/01.MSS.0000161804.05399.3B] [PMID: 15870626]
[8]
Benatti, F.B.; Pedersen, B.K. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat. Rev. Rheumatol., 2015, 11(2), 86-97.
[http://dx.doi.org/10.1038/nrrheum.2014.193] [PMID: 25422002]
[9]
Mauer, J.; Chaurasia, B.; Goldau, J.; Vogt, M.C.; Ruud, J.; Nguyen, K.D.; Theurich, S.; Hausen, A.C.; Schmitz, J.; Brönneke, H.S.; Estevez, E.; Allen, T.L.; Mesaros, A.; Partridge, L.; Febbraio, M.A.; Chawla, A.; Wunderlich, F.T.; Brüning, J.C. Signaling by IL-6 promotes alter-native activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol., 2014, 15(5), 423-430.
[http://dx.doi.org/10.1038/ni.2865] [PMID: 24681566]
[10]
Batista, M.L., Jr; Rosa, J.C.; Lopes, R.D.; Lira, F.S.; Martins, E., Jr; Yamashita, A.S.; Brum, P.C.; Lancha, A.H., Jr; Lopes, A.C.; Seelaen-der, M. Exercise training changes IL-10/TNF-α ratio in the skeletal muscle of post-MI rats. Cytokine, 2010, 49(1), 102-108.
[http://dx.doi.org/10.1016/j.cyto.2009.10.007] [PMID: 19948415]
[11]
Eisenberg, S.P.; Brewer, M.T.; Verderber, E.; Heimdal, P.; Brandhuber, B.J.; Thompson, R.C. Interleukin 1 receptor antagonist is a mem-ber of the interleukin 1 gene family: Evolution of a cytokine control mechanism. Proc. Natl. Acad. Sci. USA, 1991, 88(12), 5232-5236.
[http://dx.doi.org/10.1073/pnas.88.12.5232] [PMID: 1828896]
[12]
Ip, W.K.E.; Hoshi, N.; Shouval, D.S.; Snapper, S.; Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science, 2017, 356(6337), 513-519.
[http://dx.doi.org/10.1126/science.aal3535] [PMID: 28473584]
[13]
Steensberg, A.; Fischer, C.P.; Keller, C.; Møller, K.; Pedersen, B.K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab., 2003, 285(2), E433-E437.
[http://dx.doi.org/10.1152/ajpendo.00074.2003] [PMID: 12857678]
[14]
Peppler, W.T.; Townsend, L.K.; Wright, D.C. Recent advances in the role of interleukin-6 in health and disease. Curr. Opin. Pharmacol., 2020, 52, 47-51.
[http://dx.doi.org/10.1016/j.coph.2020.04.010]
[15]
Ferguson-Smith, A.C.; Chen, Y.F.; Newman, M.S.; May, L.T.; Sehgal, P.B.; Ruddle, F.H. Regional localization of the interferon-β 2/B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21. Genomics, 1988, 2(3), 203-208.
[http://dx.doi.org/10.1016/0888-7543(88)90003-1] [PMID: 3294161]
[16]
Heinrich, P.C.; Behrmann, I.; Müller-Newen, G.; Schaper, F.; Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway1. Biochem. J., 1998, 334(2), 297-314.
[http://dx.doi.org/10.1042/bj3340297]
[17]
Pelosi, M.; De Rossi, M.; Barberi, L.; Musarò, A. IL-6 impairs myogenic differentiation by downmodulation of p90RSK/eEF2 and mTOR/p70S6K axes, without affecting AKT activity. BioMed Res. Int., 2014, 2014(206026), 206026.
[http://dx.doi.org/10.1155/2014/206026] [PMID: 24967341]
[18]
Janssen, S.P.M.; Gayan-Ramirez, G.; Van den Bergh, A.; Herijgers, P.; Maes, K.; Verbeken, E.; Decramer, M. Interleukin-6 causes myo-cardial failure and skeletal muscle atrophy in rats. Circulation, 2005, 111(8), 996-1005.
[http://dx.doi.org/10.1161/01.CIR.0000156469.96135.0D] [PMID: 15710765]
[19]
Bonetto, A.; Aydogdu, T.; Jin, X.; Zhang, Z.; Zhan, R.; Puzis, L.; Koniaris, L.G.; Zimmers, T.A. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am. J. Physiol. Endocrinol. Metab., 2012, 303(3), E410-E421.
[http://dx.doi.org/10.1152/ajpendo.00039.2012] [PMID: 22669242]
[20]
Haddad, F.; Zaldivar, F.; Cooper, D.M.; Adams, G.R. IL-6-induced skeletal muscle atrophy. J. Appl. Physiol., 2005, 98(3), 911-917.
[http://dx.doi.org/10.1152/japplphysiol.01026.2004] [PMID: 15542570]
[21]
Rui, L.; Yuan, M.; Frantz, D.; Shoelson, S.; White, M.F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem., 2002, 277(44), 42394-42398.
[http://dx.doi.org/10.1074/jbc.C200444200] [PMID: 12228220]
[22]
Hojman, P.; Brolin, C.; Nørgaard-Christensen, N.; Dethlefsen, C.; Lauenborg, B.; Olsen, C.K.; Åbom, M.M.; Krag, T.; Gehl, J.; Pedersen, B.K. IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity. Am. J. Physiol. Endocrinol. Metab., 2019, 316(5), E940-E947.
[http://dx.doi.org/10.1152/ajpendo.00414.2018] [PMID: 30779630]
[23]
Severinsen, M.C.K.; Pedersen, B.K. Muscle-organ crosstalk: The emerging roles of myokines. Endocr. Rev., 2020, 41(4), 594-609.
[http://dx.doi.org/10.1210/endrev/bnaa016] [PMID: 32393961]
[24]
Simpson, R.J.; Hammacher, A.; Smith, D.K.; Matthews, J.M.; Ward, L.D. Interleukin-6: Structure-function relationships. Protein Sci., 1997, 6(5), 929-955.
[http://dx.doi.org/10.1002/pro.5560060501] [PMID: 9144766]
[25]
Horsten, U.; Müller-Newen, G.; Gerhartz, C.; Wollmer, A.; Wijdenes, J.; Heinrich, P.C.; Grötzinger, J. Molecular modeling-guided mutage-nesis of the extracellular part of gp130 leads to the identification of contact sites in the interleukin-6 (IL-6).IL-6 receptor.gp130 complex. J. Biol. Chem., 1997, 272(38), 23748-23757.
[http://dx.doi.org/10.1074/jbc.272.38.23748] [PMID: 9295319]
[26]
Pflanz, S.; Kurth, I.; Grötzinger, J.; Heinrich, P.C.; Müller-Newen, G. Two different epitopes of the signal transducer gp130 sequentially cooperate on IL-6-induced receptor activation. J. Immunol., 2000, 165(12), 7042-7049.
[http://dx.doi.org/10.4049/jimmunol.165.12.7042] [PMID: 11120832]
[27]
Vandooren, J.; Van den Steen, P.E.; Opdenakker, G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade. Crit. Rev. Biochem. Mol. Biol., 2013, 48(3), 222-272.
[http://dx.doi.org/10.3109/10409238.2013.770819] [PMID: 23547785]
[28]
Robergs, R.A.; Ghiasvand, F.; Parker, D. Biochemistry of exercise-induced metabolic acidosis. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2004, 287(3), R502-R516.
[http://dx.doi.org/10.1152/ajpregu.00114.2004] [PMID: 15308499]
[29]
Fischer, C.P. Interleukin-6 in acute exercise and training: What is the biological relevance? Exerc. Immunol. Rev., 2006, 12(May), 6-33.
[PMID: 17201070]
[30]
Keller, P.; Keller, C.; Carey, A.L.; Jauffred, S.; Fischer, C.P.; Steensberg, A.; Pedersen, B.K. Interleukin-6 production by contracting hu-man skeletal muscle: Autocrine regulation by IL-6. Biochem. Biophys. Res. Commun., 2003, 310(2), 550-554.
[http://dx.doi.org/10.1016/j.bbrc.2003.09.048] [PMID: 14521945]
[31]
Keller, C.; Steensberg, A.; Hansen, A.K.; Fischer, C.P.; Plomgaard, P.; Pedersen, B.K. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J. Appl. Physiol., 2005, 99(6), 2075-2079.
[http://dx.doi.org/10.1152/japplphysiol.00590.2005] [PMID: 16099893]
[32]
Keller, P.; Penkowa, M.; Keller, C.; Steensberg, A.; Fischer, C.P.; Giralt, M.; Hidalgo, J.; Pedersen, B.K. Interleukin-6 receptor expression in contracting human skeletal muscle: Regulating role of IL-6. FASEB J., 2005, 19(9), 1181-1183.
[http://dx.doi.org/10.1096/fj.04-3278fje] [PMID: 15837717]
[33]
Eulenfeld, R.; Dittrich, A.; Khouri, C.; Müller, P.J.; Mütze, B.; Wolf, A.; Schaper, F. Interleukin-6 signalling: More than Jaks and STATs. Eur. J. Cell Biol., 2012, 91(6-7), 486-495.
[http://dx.doi.org/10.1016/j.ejcb.2011.09.010] [PMID: 22138086]
[34]
Nakaoka, Y.; Nishida, K.; Fujio, Y.; Izumi, M.; Terai, K.; Oshima, Y.; Sugiyama, S.; Matsuda, S.; Koyasu, S.; Yamauchi-Takihara, K.; Hirano, T.; Kawase, I.; Hirota, H. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ. Res., 2003, 93(3), 221-229.
[http://dx.doi.org/10.1161/01.RES.0000085562.48906.4A] [PMID: 12855672]
[35]
Hemmings, B.A.; Restuccia, D.F. PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol., 2012, 4(9), a011189.
[http://dx.doi.org/10.1101/cshperspect.a011189] [PMID: 22952397]
[36]
Takahashi-Tezuka, M.; Yoshida, Y.; Fukada, T.; Ohtani, T.; Yamanaka, Y.; Nishida, K.; Nakajima, K.; Hibi, M.; Hirano, T. Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. Mol. Cell. Biol., 1998, 18(7), 4109-4117.
[http://dx.doi.org/10.1128/MCB.18.7.4109] [PMID: 9632795]
[37]
Alessi, D.R.; James, S.R.; Downes, C.P.; Holmes, A.B.; Gaffney, P.R.J.; Reese, C.B.; Cohen, P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr. Biol., 1997, 7(4), 261-269.
[http://dx.doi.org/10.1016/S0960-9822(06)00122-9] [PMID: 9094314]
[38]
Scheid, M.P.; Woodgett, J.R. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett., 2003, 546(1), 108-112.
[http://dx.doi.org/10.1016/S0014-5793(03)00562-3] [PMID: 12829245]
[39]
Weigert, C.; Hennige, A.M.; Brodbeck, K.; Häring, H.U.; Schleicher, E.D. Interleukin-6 acts as insulin sensitizer on glycogen synthesis in hu-man skeletal muscle cells by phosphorylation of Ser473 of Akt. Am. J. Physiol., 2005, 289, 251-257.
[http://dx.doi.org/10.1152/ajpendo.00448.2004]
[40]
Sano, H.; Kane, S.; Sano, E.; Mîinea, C.P.; Asara, J.M.; Lane, W.S.; Garner, C.W.; Lienhard, G.E. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem., 2003, 278(17), 14599-14602.
[http://dx.doi.org/10.1074/jbc.C300063200] [PMID: 12637568]
[41]
Mîinea, C.P.; Sano, H.; Kane, S.; Sano, E.; Fukuda, M.; Peränen, J.; Lane, W.S.; Lienhard, G.E. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J., 2005, 391(Pt 1), 87-93.
[http://dx.doi.org/10.1042/BJ20050887] [PMID: 15971998]
[42]
Lauritzen, H.P.M.M. In vivo imaging of GLUT4 translocation. Appl. Physiol. Nutr. Metab., 2009, 34(3), 420-423.
[http://dx.doi.org/10.1139/H09-043] [PMID: 19448708]
[43]
Zerial, M.; McBride, H. Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol., 2001, 2(2), 107-117.
[http://dx.doi.org/10.1038/35052055] [PMID: 11252952]
[44]
Sun, Y.; Bilan, P.J.; Liu, Z.; Klip, A. Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells. Proc. Natl. Acad. Sci. USA, 2010, 107(46), 19909-19914.
[http://dx.doi.org/10.1073/pnas.1009523107] [PMID: 21041651]
[45]
Kelly, M.; Keller, C.; Avilucea, P.R.; Keller, P.; Luo, Z.; Xiang, X.; Giralt, M.; Hidalgo, J.; Saha, A.K.; Pedersen, B.K.; Ruderman, N.B. AMPK activity is diminished in tissues of IL-6 knockout mice: The effect of exercise. Biochem. Biophys. Res. Commun., 2004, 320(2), 449-454.
[http://dx.doi.org/10.1016/j.bbrc.2004.05.188] [PMID: 15219849]
[46]
Schweitzer, G.G.; Arias, E.B.; Cartee, G.D. Sustained postexercise increases in AS160 Thr642 and Ser588 phosphorylation in skeletal muscle without sustained increases in kinase phosphorylation. J. Appl. Physiol., 2012, 113(12), 1852-1861.
[http://dx.doi.org/10.1152/japplphysiol.00619.2012] [PMID: 22936728]
[47]
Jensen, J.; Lai, Y-C. Regulation of muscle glycogen synthase phosphorylation and kinetic properties by insulin, exercise, adrenaline and role in insulin resistance. Arch. Physiol. Biochem., 2009, 115(1), 13-21.
[http://dx.doi.org/10.1080/13813450902778171] [PMID: 19267278]
[48]
Shulman, R.G. Glycogen turnover forms lactate during exercise. Exerc. Sport Sci. Rev., 2005, 33(4), 157-162.
[http://dx.doi.org/10.1097/00003677-200510000-00002] [PMID: 16239831]
[49]
Dutka, T.L.; Lamb, G.D. Na+-K+ pumps in the transverse tubular system of skeletal muscle fibers preferentially use ATP from glycolysis. Am. J. Physiol. Cell Physiol., 2007, 293(3), C967-C977.
[http://dx.doi.org/10.1152/ajpcell.00132.2007] [PMID: 17553934]
[50]
Stephenson, D.G. Tubular system excitability: An essential component of excitation-contraction coupling in fast-twitch fibres of vertebrate skeletal muscle. J. Muscle Res. Cell Motil., 2006, 27(5-7), 259-274.
[http://dx.doi.org/10.1007/s10974-006-9073-6] [PMID: 16874453]
[51]
Ørtenblad, N.; Westerblad, H.; Nielsen, J. Muscle glycogen stores and fatigue. J. Physiol., 2013, 591(18), 4405-4413.
[http://dx.doi.org/10.1113/jphysiol.2013.251629] [PMID: 23652590]
[52]
Ørtenblad, N.; Nielsen, J. Muscle glycogen and cell function--Location, location, location. Scand. J. Med. Sci. Sports, 2015, 25(Suppl. 4), 34-40.
[http://dx.doi.org/10.1111/sms.12599] [PMID: 26589115]
[53]
Gao, S.; Durstine, J.L.; Koh, H-J.; Carver, W.E.; Frizzell, N.; Carson, J.A. Acute myotube protein synthesis regulation by IL-6-related cytokines. Am. J. Physiol. Cell Physiol., 2017, 313(5), C487-C500.
[http://dx.doi.org/10.1152/ajpcell.00112.2017] [PMID: 28768641]
[54]
Goodman, C.A. Role of mTORC1 in mechanically induced increases in translation and skeletal muscle mass. J. Appl. Physiol., 2019, 127(2), 581-590.
[http://dx.doi.org/10.1152/japplphysiol.01011.2018] [PMID: 30676865]
[55]
Marcotte, G.R.; West, D.W.D.; Baar, K. The molecular basis for load-induced skeletal muscle hypertrophy. Calcif. Tissue Int., 2015, 96(3), 196-210.
[http://dx.doi.org/10.1007/s00223-014-9925-9] [PMID: 25359125]
[56]
Kakumoto, K.; Ikeda, J.; Okada, M.; Morii, E.; Oneyama, C. MLST8 promotes mTOR-mediated tumor progression. PLoS One, 2015, 10(4), e0119015.
[http://dx.doi.org/10.1371/journal.pone.0119015] [PMID: 25906254]
[57]
Yang, H.; Jiang, X.; Li, B.; Yang, H.J.; Miller, M.; Yang, A.; Dhar, A.; Pavletich, N.P. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature, 2017, 552(7685), 368-373.
[http://dx.doi.org/10.1038/nature25023] [PMID: 29236692]
[58]
Sancak, Y.; Thoreen, C.C.; Peterson, T.R.; Lindquist, R.A.; Kang, S.A.; Spooner, E.; Carr, S.A.; Sabatini, D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell, 2007, 25(6), 903-915.
[http://dx.doi.org/10.1016/j.molcel.2007.03.003] [PMID: 17386266]
[59]
Nascimento, E.B.M.; Snel, M.; Guigas, B.; van der Zon, G.C.M.; Kriek, J.; Maassen, J.A.; Jazet, I.M.; Diamant, M.; Ouwens, D.M. Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1. Cell. Signal., 2010, 22(6), 961-967.
[http://dx.doi.org/10.1016/j.cellsig.2010.02.002] [PMID: 20138985]
[60]
Wiza, C.; Nascimento, E.B.M.; Ouwens, D.M. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am. J. Physiol. Endocrinol. Metab., 2012, 302(12), E1453-E1460.
[http://dx.doi.org/10.1152/ajpendo.00660.2011] [PMID: 22354785]
[61]
Gao, D.; Inuzuka, H.; Tan, M.K.M.; Fukushima, H.; Locasale, J.W.; Liu, P.; Wan, L.; Zhai, B.; Chin, Y.R.; Shaik, S.; Lyssiotis, C.A.; Gygi, S.P.; Toker, A.; Cantley, L.C.; Asara, J.M.; Harper, J.W.; Wei, W. mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR. Mol. Cell, 2011, 44(2), 290-303.
[http://dx.doi.org/10.1016/j.molcel.2011.08.030] [PMID: 22017875]
[62]
Zhao, Y.; Xiong, X.; Sun, Y. DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy. Mol. Cell, 2011, 44(2), 304-316.
[http://dx.doi.org/10.1016/j.molcel.2011.08.029] [PMID: 22017876]
[63]
Catena, V.; Fanciulli, M. Deptor: Not only a mTOR inhibitor. J. Exp. Clin. Cancer Res., 2017, 36(1), 12.
[http://dx.doi.org/10.1186/s13046-016-0484-y] [PMID: 28086984]
[64]
Duan, S.; Skaar, J.R.; Kuchay, S.; Toschi, A.; Kanarek, N.; Ben-Neriah, Y.; Pagano, M. mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR. Mol. Cell, 2011, 44(2), 317-324.
[http://dx.doi.org/10.1016/j.molcel.2011.09.005] [PMID: 22017877]
[65]
Dibble, C.C.; Manning, B.D. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol., 2013, 15(6), 555-564.
[http://dx.doi.org/10.1038/ncb2763] [PMID: 23728461]
[66]
Tee, A.R.; Manning, B.D.; Roux, P.P.; Cantley, L.C.; Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol., 2003, 13(15), 1259-1268.
[http://dx.doi.org/10.1016/S0960-9822(03)00506-2] [PMID: 12906785]
[67]
Dibble, C.C.; Elis, W.; Menon, S.; Qin, W.; Klekota, J.; Asara, J.M.; Finan, P.M.; Kwiatkowski, D.J.; Murphy, L.O.; Manning, B.D. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell, 2012, 47(4), 535-546.
[http://dx.doi.org/10.1016/j.molcel.2012.06.009] [PMID: 22795129]
[68]
Menon, S.; Dibble, C.C.; Talbott, G.; Hoxhaj, G.; Valvezan, A.J.; Takahashi, H.; Cantley, L.C.; Manning, B.D. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell, 2014, 156(4), 771-785.
[http://dx.doi.org/10.1016/j.cell.2013.11.049] [PMID: 24529379]
[69]
Anandapadamanaban, M.; Masson, G.R.; Perisic, O.; Berndt, A.; Kaufman, J.; Johnson, C.M.; Santhanam, B.; Rogala, K.B.; Sabatini, D.M.; Williams, R.L. Architecture of human Rag GTPase heterodimers and their complex with mTORC1. Science, 2019, 366(6462), 203-210.
[http://dx.doi.org/10.1126/science.aax3939] [PMID: 31601764]
[70]
Sancak, Y.; Peterson, T.R.; Shaul, Y.D.; Lindquist, R.A.; Thoreen, C.C.; Bar-Peled, L.; Sabatini, D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 2008, 320(5882), 1496-1501.
[http://dx.doi.org/10.1126/science.1157535] [PMID: 18497260]
[71]
Bar-Peled, L.; Schweitzer, L.D.; Zoncu, R.; Sabatini, D.M. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell, 2012, 150(6), 1196-1208.
[http://dx.doi.org/10.1016/j.cell.2012.07.032] [PMID: 22980980]
[72]
Nada, S.; Hondo, A.; Kasai, A.; Koike, M.; Saito, K.; Uchiyama, Y.; Okada, M. The novel lipid raft adaptor p18 controls endosome dyna-mics by anchoring the MEK-ERK pathway to late endosomes. EMBO J., 2009, 28(5), 477-489.
[http://dx.doi.org/10.1038/emboj.2008.308] [PMID: 19177150]
[73]
Sancak, Y.; Bar-Peled, L.; Zoncu, R.; Markhard, A.L.; Nada, S.; Sabatini, D.M. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 2010, 141(2), 290-303.
[http://dx.doi.org/10.1016/j.cell.2010.02.024] [PMID: 20381137]
[74]
Zoncu, R.; Bar-Peled, L.; Efeyan, A.; Wang, S.; Sancak, Y.; Sabatini, D.M. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science, 2011, 334(6056), 678-683.
[http://dx.doi.org/10.1126/science.1207056] [PMID: 22053050]
[75]
Richter, J.D.; Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature, 2005, 433(7025), 477-480.
[http://dx.doi.org/10.1038/nature03205] [PMID: 15690031]
[76]
Holz, M.K.; Ballif, B.A.; Gygi, S.P.; Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell, 2005, 123(4), 569-580.
[http://dx.doi.org/10.1016/j.cell.2005.10.024] [PMID: 16286006]
[77]
Harms, U.; Andreou, A.Z.; Gubaev, A.; Klostermeier, D. eIF4B, eIF4G and RNA regulate eIF4A activity in translation initiation by modu-lating the eIF4A conformational cycle. Nucleic Acids Res., 2014, 42(12), 7911-7922.
[http://dx.doi.org/10.1093/nar/gku440] [PMID: 24848014]
[78]
Wang, X.; Proud, C.G. The mTOR pathway in the control of protein synthesis. Physiology (Bethesda), 2006, 21(5), 362-369.
[http://dx.doi.org/10.1152/physiol.00024.2006] [PMID: 16990457]
[79]
Jackson, R.J.; Hellen, C.U.T.; Pestova, T.V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol., 2010, 11(2), 113-127.
[http://dx.doi.org/10.1038/nrm2838] [PMID: 20094052]
[80]
Villa, N.; Do, A.; Hershey, J.W.B.; Fraser, C.S. Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promo-te mRNA recruitment to the ribosome. J. Biol. Chem., 2013, 288(46), 32932-32940.
[http://dx.doi.org/10.1074/jbc.M113.517011] [PMID: 24092755]
[81]
Hinnebusch, A.G. Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol. Mol. Biol. Rev., 2011, 75(3), 434-467.
[http://dx.doi.org/10.1128/MMBR.00008-11] [PMID: 21885680]
[82]
Spirin, A.S. How does a scanning ribosomal particle move along the 5′-untranslated region of eukaryotic mRNA? Brownian Ratchet mo-del. Biochemistry, 2009, 48(45), 10688-10692.
[http://dx.doi.org/10.1021/bi901379a] [PMID: 19835415]
[83]
van Gorp, A.G.M.; van der Vos, K.E.; Brenkman, A.B.; Bremer, A.; van den Broek, N.; Zwartkruis, F.; Hershey, J.W.; Burgering, B.M.; Calkhoven, C.F.; Coffer, P.J. AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene, 2009, 28(1), 95-106.
[http://dx.doi.org/10.1038/onc.2008.367] [PMID: 18836482]
[84]
Raught, B.; Peiretti, F.; Gingras, A.C.; Livingstone, M.; Shahbazian, D.; Mayeur, G.L.; Polakiewicz, R.D.; Sonenberg, N.; Hershey, J.W. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J., 2004, 23(8), 1761-1769.
[http://dx.doi.org/10.1038/sj.emboj.7600193] [PMID: 15071500]
[85]
Figueiredo, V.C.; McCarthy, J.J. Regulation of ribosome biogenesis in skeletal muscle hypertrophy. Physiology (Bethesda), 2019, 34(1), 30-42.
[http://dx.doi.org/10.1152/physiol.00034.2018] [PMID: 30540235]
[86]
Grummt, I. Life on a planet of its own: Regulation of RNA polymerase I transcription in the nucleolus. Genes Dev., 2003, 17(14), 1691-1702.
[http://dx.doi.org/10.1101/gad.1098503R] [PMID: 12865296]
[87]
Mayer, C.; Zhao, J.; Yuan, X.; Grummt, I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev., 2004, 18(4), 423-434.
[http://dx.doi.org/10.1101/gad.285504] [PMID: 15004009]
[88]
von Walden, F.; Liu, C.; Aurigemma, N.; Nader, G.A. mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling. Am. J. Physiol. Cell Physiol., 2016, 311(4), C663-C672.
[http://dx.doi.org/10.1152/ajpcell.00144.2016] [PMID: 27581648]
[89]
Hannan, K.M.; Brandenburger, Y.; Jenkins, A.; Sharkey, K.; Cavanaugh, A.; Rothblum, L.; Moss, T.; Poortinga, G.; McArthur, G.A.; Pear-son, R.B.; Hannan, R.D. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol., 2003, 23(23), 8862-8877.
[http://dx.doi.org/10.1128/MCB.23.23.8862-8877.2003] [PMID: 14612424]
[90]
Goodfellow, S.J. Zomerdijk, JCBM Basic mechanisms in RNA polymerase I transcription of the ribosomal RNA genes. Subcell. Biochem., 2013, 61, 211-236.
[91]
Tschochner, H.; Hurt, E. Pre-ribosomes on the road from the nucleolus to the cytoplasm. Trends Cell Biol., 2003, 13(5), 255-263.
[http://dx.doi.org/10.1016/S0962-8924(03)00054-0] [PMID: 12742169]
[92]
Jorgensen, P.; Rupes, I.; Sharom, J.R.; Schneper, L.; Broach, J.R.; Tyers, M. A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev., 2004, 18(20), 2491-2505.
[http://dx.doi.org/10.1101/gad.1228804] [PMID: 15466158]
[93]
Marion, R.M.; Regev, A.; Segal, E.; Barash, Y.; Koller, D.; Friedman, N.; O’Shea, E.K. Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. Proc. Natl. Acad. Sci. USA, 2004, 101(40), 14315-14322.
[http://dx.doi.org/10.1073/pnas.0405353101] [PMID: 15353587]
[94]
Rudra, D.; Zhao, Y.; Warner, J.R. Central role of Ifh1p-Fhl1p interaction in the synthesis of yeast ribosomal proteins. EMBO J., 2005, 24(3), 533-542.
[http://dx.doi.org/10.1038/sj.emboj.7600553] [PMID: 15692568]
[95]
Kantidakis, T.; Ramsbottom, B.A.; Birch, J.L.; Dowding, S.N.; White, R.J. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc. Natl. Acad. Sci. USA, 2010, 107(26), 11823-11828.
[http://dx.doi.org/10.1073/pnas.1005188107] [PMID: 20543138]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy