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Actions of Insulin As a Survival and Growth Factor: Akt, mTOR, and Regulation of Translation

  • Luc Furic
  • Mark Livingstone
  • Ivan Topisirovic
  • Nahum SonenbergEmail author
Chapter
Part of the Energy Balance and Cancer book series (EBAC, volume 1)

Abstract

Binding of insulin to the insulin receptor (IR) stimulates the receptor’s tyrosine kinase activity. IR activation leads to the recruitment of key activators of downstream pathways via the insulin receptor substrate (IRS) proteins. In a similar fashion, the insulin growth factor-1 receptor (IGF1R) transduces signals to downstream effectors via the PI3K and MAPK pathways.

Keywords

eIF4F Complex Terminal Pleckstrin Homology Regulate Translation Elongation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was funded by Canadian Cancer Society grant 016208 to NS. LF is a Research Fellow of The Terry Fox Foundation through an award from the National Cancer Institute of Canada (Award #019676) and also received support from the USARMY PCRP Award#W81XWH-10-1-0357. M.L. is a Research Student of the Terry Fox Foundation (Award #700029).

References

  1. 1.
    Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA (2006) Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol 26:8042–8051PubMedCrossRefGoogle Scholar
  2. 2.
    Yang ZZ, Tschopp O, Di-Poi N, Bruder E, Baudry A, Dummler B, Wahli W, Hemmings BA (2005) Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol 25:10407–10418PubMedCrossRefGoogle Scholar
  3. 3.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedCrossRefGoogle Scholar
  4. 4.
    Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34:620–627PubMedCrossRefGoogle Scholar
  5. 5.
    Partovian C, Ju R, Zhuang ZW, Martin KA, Simons M (2008) Syndecan-4 regulates subcellular localization of mTOR Complex2 and Akt activation in a PKCalpha-dependent manner in endothelial cells. Mol Cell 32:140–149PubMedCrossRefGoogle Scholar
  6. 6.
    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 127:125–137PubMedCrossRefGoogle Scholar
  7. 7.
    Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665PubMedCrossRefGoogle Scholar
  8. 8.
    Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G (1997) Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385:544–548PubMedCrossRefGoogle Scholar
  9. 9.
    Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN, Hay N (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11:701–713PubMedCrossRefGoogle Scholar
  10. 10.
    Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86PubMedCrossRefGoogle Scholar
  11. 11.
    Hu C, Pang S, Kong X, Velleca M, Lawrence JC Jr (1994) Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci U S A 91:3730–3734PubMedCrossRefGoogle Scholar
  12. 12.
    Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB (2007) Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25:209–226PubMedCrossRefGoogle Scholar
  13. 13.
    Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G (2000) Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408:994–997PubMedCrossRefGoogle Scholar
  14. 14.
    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 328:1172–1176PubMedCrossRefGoogle Scholar
  15. 15.
    Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, Sonenberg N, Kelly PA, Sotiropoulos A, Pende M (2005) Atrophy of S6K1(−/−) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol 7:286–294PubMedCrossRefGoogle Scholar
  16. 16.
    Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G (2004) S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24:3112–3124PubMedCrossRefGoogle Scholar
  17. 17.
    Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A 98:9666–9670PubMedCrossRefGoogle Scholar
  18. 18.
    Liu S, Okada T, Assmann A, Soto J, Liew CW, Bugger H, Shirihai OS, Abel ED, Kulkarni RN (2009) Insulin signaling regulates mitochondrial function in pancreatic beta-cells. PLoS ONE 4:e7983PubMedCrossRefGoogle Scholar
  19. 19.
    Pardo OE, Wellbrock C, Khanzada UK, Aubert M, Arozarena I, Davidson S, Bowen F, Parker PJ, Filonenko VV, Gout IT, Sebire N, Marais R, Downward J, Seckl MJ (2006) FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2. EMBO J 25:3078–3088PubMedCrossRefGoogle Scholar
  20. 20.
    Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M (2006) S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314:467–471PubMedCrossRefGoogle Scholar
  21. 21.
    Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW (2004) Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J 23:1761–1769PubMedCrossRefGoogle Scholar
  22. 22.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321PubMedCrossRefGoogle Scholar
  23. 23.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedCrossRefGoogle Scholar
  24. 24.
    del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689PubMedCrossRefGoogle Scholar
  25. 25.
    Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337PubMedCrossRefGoogle Scholar
  26. 26.
    Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM (2004) Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 279:21085–21095PubMedCrossRefGoogle Scholar
  27. 27.
    Grant S (2008) Cotargeting survival signaling pathways in cancer. J Clin Invest 118:3003–3006PubMedCrossRefGoogle Scholar
  28. 28.
    Qi XJ, Wildey GM, Howe PH (2006) Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 281:813–823PubMedCrossRefGoogle Scholar
  29. 29.
    Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG, Tsang BK, Cheng JQ (2004) Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279:5405–5412PubMedCrossRefGoogle Scholar
  30. 30.
    Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885PubMedCrossRefGoogle Scholar
  31. 31.
    Hu Y, Yao J, Liu Z, Liu X, Fu H, Ye K (2005) Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation. EMBO J 24:3543–3554PubMedCrossRefGoogle Scholar
  32. 32.
    King FW, Skeen J, Hay N, Shtivelman E (2004) Inhibition of Chk1 by activated PKB/Akt. Cell Cycle 3:634–637PubMedGoogle Scholar
  33. 33.
    Shtivelman E, Sussman J, Stokoe D (2002) A role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle. Curr Biol 12:919–924PubMedCrossRefGoogle Scholar
  34. 34.
    Kim AH, Khursigara G, Sun X, Franke TF, Chao MV (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21:893–901PubMedCrossRefGoogle Scholar
  35. 35.
    Barthwal MK, Sathyanarayana P, Kundu CN, Rana B, Pradeep A, Sharma C, Woodgett JR, Rana A (2003) Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival. J Biol Chem 278:3897–3902PubMedCrossRefGoogle Scholar
  36. 36.
    Biggs WH III, Meisenhelder J, Hunter T, Cavenee WK, Arden KC (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci U S A 96:7421–7426PubMedCrossRefGoogle Scholar
  37. 37.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedCrossRefGoogle Scholar
  38. 38.
    Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398:630–634PubMedCrossRefGoogle Scholar
  39. 39.
    Pugazhenthi S, Khandelwal RL (1995) Regulation of glycogen synthase activation in isolated hepatocytes. Mol Cell Biochem 149–150:95–101PubMedCrossRefGoogle Scholar
  40. 40.
    Beurel E, Jope RS (2006) The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 79:173–189PubMedCrossRefGoogle Scholar
  41. 41.
    Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK (2007) Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 104:6247–6252PubMedCrossRefGoogle Scholar
  42. 42.
    Beurel E, Kornprobst M, Blivet-Van Eggelpoel MJ, Ruiz-Ruiz C, Cadoret A, Capeau J, Desbois-Mouthon C (2004) GSK-3beta inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression. Exp Cell Res 300:354–364PubMedCrossRefGoogle Scholar
  43. 43.
    Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem 278:48872–48879PubMedCrossRefGoogle Scholar
  44. 44.
    Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS (2002) Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. Proc Natl Acad Sci U S A 99:7951–7955PubMedCrossRefGoogle Scholar
  45. 45.
    Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406:86–90PubMedCrossRefGoogle Scholar
  46. 46.
    Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963PubMedCrossRefGoogle Scholar
  47. 47.
    Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852–2864PubMedCrossRefGoogle Scholar
  48. 48.
    Polunovsky VA, Rosenwald IB, Tan AT, White J, Chiang L, Sonenberg N, Bitterman PB (1996) Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc. Mol Cell Biol 16:6573–6581PubMedGoogle Scholar
  49. 49.
    Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:332–337PubMedCrossRefGoogle Scholar
  50. 50.
    Wendel HG, Malina A, Zhao Z, Zender L, Kogan SC, Cordon-Cardo C, Pelletier J, Lowe SW (2006) Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res 66:7639–7646PubMedCrossRefGoogle Scholar
  51. 51.
    De Benedetti A, Joshi-Barve S, Rinker-Schaeffer C, Rhoads RE (1991) Expression of antisense RNA against initiation factor eIF-4E mRNA in HeLa cells results in lengthened cell division times, diminished translation rates, and reduced levels of both eIF-4E and the p220 component of eIF-4F. Mol Cell Biol 11:5435–5445PubMedGoogle Scholar
  52. 52.
    Polunovsky VA, Gingras AC, Sonenberg N, Peterson M, Tan A, Rubins JB, Manivel JC, Bitterman PB (2000) Translational control of the antiapoptotic function of Ras. J Biol Chem 275:24776–24780PubMedCrossRefGoogle Scholar
  53. 53.
    Herbert TP, Fahraeus R, Prescott A, Lane DP, Proud CG (2000) Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol 10:793–796PubMedCrossRefGoogle Scholar
  54. 54.
    Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G (2007) Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128:257–267PubMedCrossRefGoogle Scholar
  55. 55.
    Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, Schwier P, Capen A, Goode RL, Dowless MS, Chen Y, Zhang H, Sissons S, Cox K, McNulty AM, Parsons SH, Wang T, Sams L, Geeganage S, Douglass LE, Neubauer BL, Dean NM, Blanchard K, Shou J, Stancato LF, Carter JH, Marcusson EG (2007) Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest 117:2638–2648PubMedCrossRefGoogle Scholar
  56. 56.
    Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433:477–480PubMedCrossRefGoogle Scholar
  57. 57.
    De Benedetti A, Graff JR (2004) eIF-4E expression and its role in malignancies and metastases. Oncogene 23:3189–3199PubMedCrossRefGoogle Scholar
  58. 58.
    Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC (2003) Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 12:889–901PubMedCrossRefGoogle Scholar
  59. 59.
    Holcik M, Gordon BW, Korneluk RG (2003) The internal ribosome entry site-mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2. Mol Cell Biol 23:280–288PubMedCrossRefGoogle Scholar
  60. 60.
    Kim YK, Back SH, Rho J, Lee SH, Jang SK (2001) La autoantigen enhances translation of BiP mRNA. Nucleic Acids Res 29:5009–5016PubMedCrossRefGoogle Scholar
  61. 61.
    Brenet F, Socci ND, Sonenberg N, Holland EC (2009) Akt phosphorylation of La regulates specific mRNA translation in glial progenitors. Oncogene 28:128–139PubMedCrossRefGoogle Scholar
  62. 62.
    Evdokimova V, Ruzanov P, Anglesio MS, Sorokin AV, Ovchinnikov LP, Buckley J, Triche TJ, Sonenberg N, Sorensen PH (2006) Akt-mediated YB-1 phosphorylation activates translation of silent mRNA species. Mol Cell Biol 26:277–292PubMedCrossRefGoogle Scholar
  63. 63.
    Palamarchuk A, Efanov A, Maximov V, Aqeilan RI, Croce CM, Pekarsky Y (2005) Akt phosphorylates and regulates Pdcd4 tumor suppressor protein. Cancer Res 65:11282–11286PubMedCrossRefGoogle Scholar
  64. 64.
    LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH (2007) Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol 27:147–156PubMedCrossRefGoogle Scholar
  65. 65.
    Benjamin D, Schmidlin M, Min L, Gross B, Moroni C (2006) BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites. Mol Cell Biol 26:9497–9507PubMedCrossRefGoogle Scholar
  66. 66.
    Gherzi R, Trabucchi M, Ponassi M, Ruggiero T, Corte G, Moroni C, Chen CY, Khabar KS, Andersen JS, Briata P (2006) The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling. PLoS Biol 5:e5PubMedCrossRefGoogle Scholar
  67. 67.
    Graham JR, Hendershott MC, Terragni J, Cooper GM (2010) mRNA degradation plays a significant role in the program of gene expression regulated by PI 3-kinase signaling. Mol Cell Biol 30(22):5295–5305PubMedCrossRefGoogle Scholar
  68. 68.
    Auld GC, Campbell DG, Morrice N, Cohen P (2005) Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. Biochem J 389:775–783PubMedCrossRefGoogle Scholar
  69. 69.
    Mathews MB, Sonenberg N, Hershey JWB (2007) Translational control in biology and medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, p 934Google Scholar
  70. 70.
    Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745PubMedCrossRefGoogle Scholar
  71. 71.
    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633PubMedCrossRefGoogle Scholar
  72. 72.
    Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406–409PubMedCrossRefGoogle Scholar
  73. 73.
    Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7:1165–1176PubMedCrossRefGoogle Scholar
  74. 74.
    Jefferson LS, Fabian JR, Kimball SR (1999) Glycogen synthase kinase-3 is the predominant insulin-regulated eukaryotic initiation factor 2B kinase in skeletal muscle. Int J Biochem Cell Biol 31:191–200PubMedCrossRefGoogle Scholar
  75. 75.
    Welsh GI, Miller CM, Loughlin AJ, Price NT, Proud CG (1998) Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett 421:125–130PubMedCrossRefGoogle Scholar
  76. 76.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedCrossRefGoogle Scholar
  77. 77.
    Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD (2006) S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell 24:185–197PubMedCrossRefGoogle Scholar
  78. 78.
    Wang X, Janmaat M, Beugnet A, Paulin FE, Proud CG (2002) Evidence that the dephosphorylation of Ser(535) in the epsilon-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin. Biochem J 367:475–481PubMedCrossRefGoogle Scholar
  79. 79.
    Nairn AC, Matsushita M, Nastiuk K, Horiuchi A, Mitsui K, Shimizu Y, Palfrey HC (2001) Elongation factor-2 phosphorylation and the regulation of protein synthesis by calcium. Prog Mol Subcell Biol 27:91–129PubMedGoogle Scholar
  80. 80.
    Traugh JA (2001) Insulin, phorbol ester and serum regulate the elongation phase of protein synthesis. Prog Mol Subcell Biol 26:33–48PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Luc Furic
    • 1
  • Mark Livingstone
    • 2
  • Ivan Topisirovic
    • 2
  • Nahum Sonenberg
    • 3
    Email author
  1. 1.Department of Anatomy and developmental biologyMonash UniversityClaytonAustralia
  2. 2.Department of Biochemistry and Goodman Cancer CentreMcGill UniversityMontréalCanada
  3. 3.Department of Biochemistry and Goodman Cancer CentreMcGill UniversityMontréalCanada

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