Control of Protein Synthesis by Insulin

  • Joseph F. Christian
  • John C. LawrenceJr.


The stimulation of protein synthesis is a classic action of insulin. 1, 2, 3 Loss of the stimulatory effect of insulin on protein synthesis contributes to the cessation of growth and weight loss, which are hallmarks of untreated Type 1 diabetes mellitus. The effect of insulin on protein metabolism is complex and involves changes in both synthesis and degradation.1, 2, 3 In some cell types an increase in rate of protein synthesis may be detected within minutes of insulin treatment. This response to insulin occurs within a timeframe comparable to that of other acute actions of the hormone, such as the activation of glucose transport and glycogen synthase activation. The rapid effects of insulin on protein synthesis involve increases in mRNA translation, the process through which the genetic code transcribed in the mRNA template is translated into protein.


Initiation Factor Internal Ribosomal Entry Site Eukaryotic Initiation Factor Internal Ribosomal Entry Site Element eEF2 Kinase 
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.


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  1. 1.
    Kimball SR, Farrell PA, Jefferson LS. Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. J Appl Physiol 2002; 93(3):1168–80.PubMedGoogle Scholar
  2. 2.
    Proud CG, Denton RM. Molecular mechanisms for the control of translation by insulin. Bio Chem J 1997; 328(Pt 2):329–41.Google Scholar
  3. 3.
    O’Brien RM, Granner DK. Gene Regulation. In: Leroith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia: Lippincott Williams and Wilkins, 2000:291–312.Google Scholar
  4. 4.
    Hershey JW. Translational control in mammalian cells. Annu Rev Biochem 1991; 60:717–755.PubMedGoogle Scholar
  5. 5.
    Merrick WC. Mechanism and regulation of eukaryotic protein synthesis. Microbiol Rev 1992; 56(2):291–315.PubMedGoogle Scholar
  6. 6.
    van der Velden AW, Thomas AA. The role of the 5′ untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol 1999; 31(1):87–106.PubMedGoogle Scholar
  7. 7.
    Manzella JM, Rychlik W, Rhoads RE et al. Insulin induction of ornithine decarboxylase. Importance of mRNA secondary structure and phosphorylation of eucaryotic initiation factors eIF-4B and eIF-4E. J Biol Chem 1991; 266(4):2383–9.PubMedGoogle Scholar
  8. 8.
    Kozak M. Influences of mRNA secondary structure on initiation by eukaryotic ribosomes. Proc Natl Acad Sci USA 1986; 83(9):2850–2854.PubMedGoogle Scholar
  9. 9.
    Meyuhas O. Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem 2000; 267(21):6321–6330.PubMedGoogle Scholar
  10. 10.
    Loreni F, Thomas G, Amaldi F. Transcription inhibitors stimulate translation of 5′ TOP mRNAs through activation of S6 kinase and the mTOR/FRAP signalling pathway. Eur J Bio Chem 2000; 267(22):6594–6601.Google Scholar
  11. 11.
    Tang H, Hornstein E, Stolovich M et al. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol 2001; 21(24):8671–8683.PubMedGoogle Scholar
  12. 12.
    Sonenberg N. Picornavirus RNA translation continues to surprise. Trends Genet 1991; 7(4):105–106.PubMedGoogle Scholar
  13. 13.
    Vagner S, Galy B, Pyronnet S. Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. EMBO Rep 2001; 2(10):893–898.PubMedGoogle Scholar
  14. 14.
    Creancier L, Morello D, Mercier P et al. Fibroblast growth factor 2 internal ribosome entry site (IRES) activity ex vivo and in transgenic mice reveals a stringent tissue-specific regulation. J Cell Biol 2000; 150(1):275–281.PubMedGoogle Scholar
  15. 15.
    Huez I, Creancier L, Audigier S et al. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol 1998; 18(11):6178–6190.PubMedGoogle Scholar
  16. 16.
    Nissen P, Hansen J, Ban N et al. The structural basis of ribosome activity in peptide bond synthesis. Science 2000; 289(5481):920–930.PubMedGoogle Scholar
  17. 17.
    Smith CJ, Rubin CS, Rosen OM. Insulin-treated 3T3-L1 adipocytes and cell-free extracts derived from them incorporate 32P into ribosomal protein S6. Proc Natl Acad Sci USA 1980; 77(5):2641–2645.PubMedGoogle Scholar
  18. 18.
    Thomas G, Siegmann M, Gordon J. Multiple phosphorylation of ribosomal protein S6 during transition of quiescent 3T3 cells into early G1, and cellular compartmentalization of the phosphate donor. Proc Natl Acad Sci USA 1979; 76(8):3952–3956.PubMedGoogle Scholar
  19. 19.
    Volarevic S, Stewart MJ, Ledermann B et al. Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science 2000; 288(5473):2045–2047.PubMedGoogle Scholar
  20. 20.
    Nygard O, Nika H. Identification by RNA-protein cross-linking of ribosomal proteins located at the interface between the small and the large subunits of mammalian ribosomes. EMBO J 1982; 1(3):357–362.PubMedGoogle Scholar
  21. 21.
    Nygard O, Nilsson L. Translational dynamics. Interactions between the translational factors, tRNA and ribosomes during eukaryotic protein synthesis. Eur J Biochem 1990; 191(1):1–17.PubMedGoogle Scholar
  22. 22.
    Thomas G. The S6 kinase signaling pathway in the control of development and growth. Biol Res 2002; 35(2):305–313.PubMedGoogle Scholar
  23. 23.
    Avruch J, Belham C, Weng Q et al. The p70 S6 kinase integrates nutrient and growth signals to control translational capacity. Prog Mol Subcell Biol 2001; 26:115–154.PubMedGoogle Scholar
  24. 24.
    Cheatham L, Monfar M, Chou MM et al. Structural and functional analysis of pp70S6k. Proc Natl Acad Sci USA 1995; 92(25):11696–11700.PubMedGoogle Scholar
  25. 25.
    Abraham RT. Identification of TOR signaling complexes: More TORC for the cell growth engine. Cell 2002; 111(1):9–12.PubMedGoogle Scholar
  26. 26.
    Majumdar R, Bandyopadhyay A, Maitra U. Mammalian translation initiation factor eIF1 functions with eIF1A and eIF3 in the formation of a stable 40 S preinitiation complex. J Biol Chem 2003; 278(8):6580–6587.PubMedGoogle Scholar
  27. 27.
    Kozak M. Pushing the limits of the scanning mechanism for initiation of translation. Gene 2002; 299(1–2):1–34.PubMedGoogle Scholar
  28. 28.
    Kozak M. The scanning model for translation: An update. J Cell Biol 1989; 108(2):229–241.PubMedGoogle Scholar
  29. 29.
    Gingras AC, Raught B, Sonenberg N. eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999; 68:913–963.PubMedGoogle Scholar
  30. 30.
    Panniers R, Rowlands AG, Henshaw EC. The effect of Mg2+ and guanine nucleotide exchange factor on the binding of guanine nucleotides to eukaryotic initiation factor 2. J Biol Chem 1988; 263(12):5519–5525.PubMedGoogle Scholar
  31. 31.
    Webb BL, Proud CG. Eukaryotic initiation factor 2B (eIF2B). Int J Biochem Cell Biol 1997; 29(10):1127–31.PubMedGoogle Scholar
  32. 32.
    Dever TE. Translation initiation: Adept at adapting. Trends Biochem Sci 1999; 24(10):398–403.PubMedGoogle Scholar
  33. 33.
    Tahara SM, Traugh JA, Sharp SB et al. Effect of hemin on site-specific phosphorylation of eukaryotic initiation factor 2. Proc Natl Acad Sci USA 1978; 75(2):789–793.PubMedGoogle Scholar
  34. 34.
    Clemens MJ, Elia A. The double-stranded RNA-dependent protein kinase PKR: Structure and function. J Interferon Cytokine Res 1997; 17(9):503–524.PubMedGoogle Scholar
  35. 35.
    Hinnebusch AG. The eIF-2 alpha kinases: Regulators of protein synthesis in starvation and stress. Semin Cell Biol 1994; 5(6):417–426.PubMedGoogle Scholar
  36. 36.
    Cherkasova VA, Hinnebusch AG. Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 2003; 17(7):859–872.PubMedGoogle Scholar
  37. 37.
    Kubota H, Obata T, Ota K et al. Rapamycin-induced translational derepression of GCN4 mRNA involves a novel mechanism for activation of the eIF2alpha kinase GCN2. J Biol Chem 2003.Google Scholar
  38. 38.
    Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397(6716):271–274.PubMedGoogle Scholar
  39. 39.
    Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: A review. Diabetes 2002; 51(Suppl 3):S455–S461.PubMedGoogle Scholar
  40. 40.
    Zhang P, McGrath B, Li S et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 2002; 22(11):3864–3874.PubMedGoogle Scholar
  41. 41.
    Proud CG. Regulation of eukaryotic initiation factor eIF2B. Prog Mol Subcell Biol 2001; 26:95–114.PubMedGoogle Scholar
  42. 42.
    Kimball SR, Horetsky RL, Jagus R et al. Expression and purification of the alpha-subunit of eukaryotic initiation factor eIF2: Use as a kinase substrate. Protein Expr Purif 1998; 12(3):415–419.PubMedGoogle Scholar
  43. 43.
    Karinch AM, Kimball SR, Vary TC et al. Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. Am J Physiol 1993; 264(1 Pt 1):E101–E108.PubMedGoogle Scholar
  44. 44.
    Welsh GI, Stokes CM, Wang X et al. Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3-kinase. FEBS Lett 1997; 410(2–3):418–22.PubMedGoogle Scholar
  45. 45.
    Welsh GI, Miller CM, Loughlin AJ et al. Regulation of eukaryotic initiation factor eIF2B: Glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett 1998; 421(2):125–30.PubMedGoogle Scholar
  46. 46.
    Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 1993; 294(Pt 3):625–9.PubMedGoogle Scholar
  47. 47.
    Cohen P, Frame S. The renaissance of GSKE. Nat Rev Mol Cell Biol 2001; 2(10):769–776.PubMedGoogle Scholar
  48. 48.
    Wang X, Janmaat M, Beugnet A et al. 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 2002; 367(Pt 2):475–481.PubMedGoogle Scholar
  49. 49.
    Lee CH, Li W, Nishimura R et al. Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc Natl Acad Sci USA 1993; 90(24):11713–11717.PubMedGoogle Scholar
  50. 50.
    Kebache S, Zuo D, Chevet E et al. Modulation of protein translation by Nck-1. Proc Natl Acad Sci USA 2002; 99(8):5406–5411.PubMedGoogle Scholar
  51. 51.
    Hershey JW, Asano K, Naranda T et al. Conservation and diversity in the structure of translation initiation factor EIF3 from humans and yeast. Biochimie 1996; 78(11–12):903–907.PubMedGoogle Scholar
  52. 52.
    Morley SJ, Traugh JA. Differential stimulation of phosphorylation of initiation factors eIF-4F, eIF-4B, eIF-3, and ribosomal protein S6 by insulin and phorbol esters. J Biol Chem 1990; 265(18):10611–6.PubMedGoogle Scholar
  53. 53.
    Wei N, Tsuge T, Serino G et al. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. Curr Biol 1998; 8(16):919–922.PubMedGoogle Scholar
  54. 54.
    Hoareau AK, Bochard V, Rety S et al. Association of the mammalian proto-oncoprotein Int-6 with the three protein complexes eIF3, COP9 signalosome and 26S proteasome. FEBS Lett 2002; 527(1–3):15–21.Google Scholar
  55. 55.
    Morris-Desbois C, Rety S, Ferro M et al. The human protein HSPC021 interacts with Int-6 and is associated with eukaryotic translation initiation factor 3. J Biol Chem 2001; 276(49):45988–45995.PubMedGoogle Scholar
  56. 56.
    Rogers Jr GW, Komar AA, Merrick WC. eIF4A: The godfather of the DEAD box helicases. Prog Nucleic Acid Res Mol Biol 2002; 72:307–331.PubMedGoogle Scholar
  57. 57.
    Lorsch JR, Herschlag D. The DEAD box protein eIF4A. 2. A cycle of nucleotide and RNA-dependent conformational changes. Biochemistry 1998; 37(8):2194–2206.PubMedGoogle Scholar
  58. 58.
    Shimogori T, Suzuki T, Kashiwagi K et al. Enhancement of helicase activity and increase of eIF-4E phosphorylation in ornithine decarboxylase-overproducing cells. Biochem Biophys Res Commun 1996; 222(3):748–752.PubMedGoogle Scholar
  59. 59.
    Pause A, Methot N, Svitkin Y et al. Dominant negative mutants of mammalian translation initiation factor eIF-4A define a critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. EMBO J 1994; 13(5):1205–1215.PubMedGoogle Scholar
  60. 60.
    Hiremath LS, Webb NR, Rhoads RE. Immunological detection of the messenger RNA cap-binding protein. J Biol Chem 1985; 260(13):7843–7849.PubMedGoogle Scholar
  61. 61.
    Duncan R, Hershey JW. Identification and quantitation of levels of protein synthesis initiation factors in crude HeLa cell lysates by two-dimensional polyacrylamide gel electrophoresis. J Biol Chem 1983; 258(11):7228–7235.PubMedGoogle Scholar
  62. 62.
    De Benedetti A, Rhoads RE. Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology. Proc Natl Acad Sci USA 1990; 87(21):8212–8216.PubMedGoogle Scholar
  63. 63.
    Pelletier J, Sonenberg N. Insertion mutagenesis to increase secondary structure within the 5’ noncoding region of a eukaryotic mRNA reduces translational efficiency. Cell 1985; 40(3):515–526.PubMedGoogle Scholar
  64. 64.
    Shibata S, Morino S, Tomoo K et al. Effect of mRNA cap structure on eIF-4E phosphorylation and cap binding analyses using Ser209-mutated eIF-4Es. Biochem Biophys Res Commun 1998; 247(2):213–216.PubMedGoogle Scholar
  65. 65.
    Whalen SG, Gingras AC, Amankwa L et al. Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins. J Biol Chem 1996; 271(20):11831–11837.PubMedGoogle Scholar
  66. 66.
    Makkinje A, Xiong H, Li M et al. Phosphorylation of eukaryotic protein synthesis initiation factor 4E by insulin-stimulated protamine kinase. J Biol Chem 1995; 270(24):14824–14828.PubMedGoogle Scholar
  67. 67.
    Waskiewicz AJ, Flynn A, Proud CG et al. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 1997; 16(8):1909–20.PubMedGoogle Scholar
  68. 68.
    Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol 2001; 21(16):5500–5511.PubMedGoogle Scholar
  69. 69.
    Pyronnet S, Imataka H, Gingras AC et al. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. EMBO J 1999; 18(1):270–279.PubMedGoogle Scholar
  70. 70.
    Minich WB, Balasta ML, Goss DJ et al. Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF-4E: Increased cap affinity of the phosphorylated form. Proc Natl Acad Sci USA 1994; 91(16):7668–7672.PubMedGoogle Scholar
  71. 71.
    Rau M, Ohlmann T, Morley SJ et al. A reevaluation of the cap-binding protein, eIF4E, as a rate-limiting factor for initiation of translation in reticulocyte lysate. J Biol Chem 1996; 271(15):8983–90.PubMedGoogle Scholar
  72. 72.
    Zuberek J, Wyslouch-Cieszynska A, Niedzwiecka A et al. Phosphorylation of eIF4E attenuates its interaction with mRNA 5’ cap analogs by electrostatic repulsion: Intein-mediated protein ligation strategy to obtain phosphorylated protein. RNA 2003; 9(1):52–61.PubMedGoogle Scholar
  73. 73.
    Scheper GC, van Kollenburg B, Hu J et al. Phosphorylation of eukaryotic initiation factor 4E markedly reduces its affinity for capped mRNA. J Biol Chem 2002; 277(5):3303–3309.PubMedGoogle Scholar
  74. 74.
    McKendrick L, Morley SJ, Pain VM et al. Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at Ser209 is not required for protein synthesis in vitro and in vivo. Eur J Biochem 2001; 268(20):5375–5385.PubMedGoogle Scholar
  75. 75.
    Lachance PE, Miron M, Raught B et al. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol Cell Biol 2002; 22(6):1656–1663.PubMedGoogle Scholar
  76. 76.
    Lawrence Jr JC, Brunn GJ. Insulin signaling and the control of PHAS-I phosphorylation. Prog Mol Subcell Biol 2001; 26:1–31.PubMedGoogle Scholar
  77. 77.
    Rousseau D, Gingras AC, Pause A et al. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 1996; 13(11):2415–2420.PubMedGoogle Scholar
  78. 78.
    Hu C, Pang S, Kong X et al. Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci USA 1994; 91(9):3730–3740.PubMedGoogle Scholar
  79. 79.
    Belsham GJ, Denton RM. The effect of insulin and adrenaline on the phosphorylation of a 22 000-molecular weight protein within isolated fat cells; possible identification as the inhibitor-1 of the ‘general phosphatase’. Biochem Soc Trans 1980; 8(3):382–383.PubMedGoogle Scholar
  80. 80.
    Pause A, Belsham GJ, Gingras AC et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5’-cap function. Nature 1994; 371(6500):762–7.PubMedGoogle Scholar
  81. 81.
    Lin TA, Kong X, Haystead TA et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 1994; 266(5185):653–6.PubMedGoogle Scholar
  82. 82.
    Youtani T, Tomoo K, Ishida T et al. Regulation of human eIF4E by 4E-BP1: Binding analysis using surface plasmon resonance. IUBMB Life 2000; 49(1):27–31.PubMedGoogle Scholar
  83. 83.
    Mader S, Lee H, Pause A et al. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mol Cell Biol 1995; 15(9):4990–7.PubMedGoogle Scholar
  84. 84.
    Haghighat A, Mader S, Pause A et al. Repression of cap-dependent translation by 4E-binding protein 1: Competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J 1995; 14(22):5701–9.PubMedGoogle Scholar
  85. 85.
    Fergusson G, Mothe-Satney I, Lawrence Jr JC. Serine phosphorylation sites in PHAS-I are dispensable for insulin stimulated dissociation from eIF4E. (In press).Google Scholar
  86. 86.
    Lin TA, Lawrence Jr JC. Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes. J Biol Chem 1996; 271(47):30199–204.PubMedGoogle Scholar
  87. 87.
    Kleijn M, Scheper GC, Wilson ML et al. Localisation and regulation of the eIF4E-binding protein 4E-BP3. FEBS Lett 2002; 532(3):319–323.PubMedGoogle Scholar
  88. 88.
    Mothe-Satney I, Brunn GJ, McMahon LP et al. Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J Biol Chem 2000; 275(43):33836–43.PubMedGoogle Scholar
  89. 89.
    Fadden P, Haystead TA, Lawrence Jr JC. Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J Biol Chem 1997; 272(15):10240–7.PubMedGoogle Scholar
  90. 90.
    Mothe-Satney I, Yang D, Fadden P et al. Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol Cell Biol 2000; 20(10):3558–67.PubMedGoogle Scholar
  91. 91.
    Gingras AC, Gygi SP, Raught B et al. Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism. Genes Dev 1999; 13(11):1422–1437.PubMedGoogle Scholar
  92. 92.
    Heesom KJ, Avison MB, Diggle TA et al. Insulin-stimulated kinase from rat fat cells that phosphorylates initiation factor 4E-binding protein 1 on the rapamycin-insensitive site (serine-111). Biochem J 1998; 336(Pt 1):39–48.PubMedGoogle Scholar
  93. 93.
    Fadden P, Haystead TA, Lawrence Jr JC. Phosphorylation of the translational regulator, PHAS-I, by protein kinase CK2. FEBS Lett 1998; 435(1):105–109.PubMedGoogle Scholar
  94. 94.
    Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 2001; 15(17):2177–2196.PubMedGoogle Scholar
  95. 95.
    Yang DQ, Kastan MB. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol 2000; 2(12):893–8.PubMedGoogle Scholar
  96. 96.
    Wang X, Li W, Parra JL et al. The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol 2003; 23(5):1546–57.PubMedGoogle Scholar
  97. 97.
    Yang D, Brunn GJ, Lawrence Jr JC. Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR. FEBS Lett 1999; 453(3):387–390.PubMedGoogle Scholar
  98. 98.
    Gingras AC, Kennedy SG, O’Leary MA et al. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 1998; 12(4):502–13.PubMedGoogle Scholar
  99. 99.
    Takata M, Ogawa W, Kitamura T et al. Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1). J Biol Chem 1999; 274(29):20611–8.PubMedGoogle Scholar
  100. 100.
    Kohn AD, Barthel A, Kovacina KS et al. Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J Biol Chem 1998; 273(19):11937–43.PubMedGoogle Scholar
  101. 101.
    Lin TA, Kong X, Saltiel AR et al. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem 1995; 270(31):18531–8.PubMedGoogle Scholar
  102. 102.
    Keiper BD, Gan W, Rhoads RE. Protein synthesis initiation factor 4G. Int J Biochem Cell Biol 1999; 31(1):37–41.PubMedGoogle Scholar
  103. 103.
    Hentze MW. eIF4G: A multipurpose ribosome adapter? Science 1997; 275(5299):500–501.PubMedGoogle Scholar
  104. 104.
    Raught B, Gingras AC, Gygi SP et al. Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 2000; 19(3):434–444.PubMedGoogle Scholar
  105. 105.
    Niedzwiecka A, Marcotrigiano J, Stepinski J et al. Biophysical studies of eIF4E cap-binding protein: Recognition of mRNA 5’ cap structure and synthetic fragments of eIF4G and 4E-BP1 proteins. J Mol Biol 2002; 319(3):615–635.PubMedGoogle Scholar
  106. 106.
    von der HT, Ball PD, McCarthy JE. Stabilization of eukaryotic initiation factor 4E binding to the mRNA 5’-Cap by domains of eIF4G. J Biol Chem 2000; 275(39):30551–30555.Google Scholar
  107. 107.
    Gan W, LaCelle M, Rhoads RE. Functional characterization of the internal ribosome entry site of eIF4G mRNA. J Biol Chem 1998; 273(9):5006–5012.PubMedGoogle Scholar
  108. 108.
    Prevot D, Darlix JL, Ohlmann T. Conducting the initiation of protein synthesis: The role of eIF4G. Biol Cell 2003; 95(3–4):141–156.PubMedGoogle Scholar
  109. 109.
    Goldstaub D, Gradi A, Bercovitch Z et al. Poliovirus 2A protease induces apoptotic cell death. Mol Cell Biol 2000; 20(4):1271–1277.PubMedGoogle Scholar
  110. 110.
    Haghighat A, Svitkin Y, Novoa I et al. The eIF4G-eIF4E complex is the target for direct cleavage by the rhinovirus 2A proteinase. J Virol 1996; 70(12):8444–8450.PubMedGoogle Scholar
  111. 111.
    Neumar RW, DeGracia DJ, Konkoly LL et al. Calpain mediates eukaryotic initiation factor 4G degradation during global brain ischemia. J Cereb Blood Flow Metab 1998; 18(8):876–881.PubMedGoogle Scholar
  112. 112.
    Ventoso I, MacMillan SE, Hershey JW et al. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett 1998; 435(1):79–83.PubMedGoogle Scholar
  113. 113.
    Das S, Maitra U. Functional significance and mechanism of eIF5-promoted GTP hydrolysis in eukaryotic translation initiation. Prog Nucleic Acid Res Mol Biol 2001; 70:207–231.PubMedGoogle Scholar
  114. 114.
    Asano K, Phan L, Valasek L et al. A multifactor complex of eIF1, eIF2, eIF3, eIF5, and tRNA (i) Met promotes initiation complex assembly and couples GTP hydrolysis to AUG recognition. Cold Spring Harb Symp Quant Biol 2001; 66:403–415.PubMedGoogle Scholar
  115. 115.
    Maiti T, Bandyopadhyay A, Maitra U. Casein kinase II phosphorylates translation initiation factor 5 (eIF5) in Saccharomyces cerevisiae. Yeast 2003; 20(2):97–108.PubMedGoogle Scholar
  116. 116.
    Browne GJ, Proud CG. Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem 2002; 269(22):5360–8.PubMedGoogle Scholar
  117. 117.
    Lodish HF, Jacobsen M. Regulation of hemoglobin synthesis. Equal rates of translation and termination of-and-globin chains. J Biol Chem 1972; 247(11):3622–3629.PubMedGoogle Scholar
  118. 118.
    Palmiter RD. Differential rates of initiation of conalbumin and ovalbumin messenger ribonucleic acid in reticulocyte lysates. J Biol Chem 1974; 249(21):6779–6787.PubMedGoogle Scholar
  119. 119.
    Slobin LI. The role of eucaryotic factor Tu in protein synthesis. The measurement of the elongation factor Tu content of rabbit reticulocytes and other mammalian cells by a sensitive radioimmunoassay. Eur J Biochem 1980; 110(2):555–563.PubMedGoogle Scholar
  120. 120.
    Chang YW, Traugh JA, Insulin stimulation of phosphorylation of elongation factor 1 (eEF-1) enhances elongation activity. Eur J Biochem 1998; 251(1–2):201–7.PubMedGoogle Scholar
  121. 121.
    Prentice GA, Merrill AR. An enzyme-linked immunosorbent assay for the association of the catalytic domain of diphthamide-specific ribosyltransferases to eukaryotic elongation factor-2. Anal Biochem 1999; 272(2):216–223.PubMedGoogle Scholar
  122. 122.
    Redpath NT, Price NT, Severinov KV et al. Regulation of elongation factor-2 by multisite phosphorylation. Eur J Biochem 1993; 213(2):689–699.PubMedGoogle Scholar
  123. 123.
    Price NT, Redpath NT, Severinov KV et al. Identification of the phosphorylation sites in elongation factor-2 from rabbit reticulocytes. FEBS Lett 1991; 282(2):253–258.PubMedGoogle Scholar
  124. 124.
    Ryazanov AG. Elongation factor-2 kinase and its newly discovered relatives. FEBS Lett 2002; 514(1):26–29.PubMedGoogle Scholar
  125. 125.
    Redpath NT, Price NT, Proud CG. Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase. J Biol Chem 1996; 271(29):17547–17554.PubMedGoogle Scholar
  126. 126.
    Redpath NT, Foulstone EJ, Proud CG. Regulation of translation elongation factor-2 insulin via a rapamycin-sensitive signalling pathway. EMBO J 1996; 15(9): 2291–7.PubMedGoogle Scholar
  127. 127.
    Wang X, Paulin FE, Campbell LE et al. Eukaryotic initiation factor 2B: Identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo. EMBO J 2001; 20(16):4349–4359.PubMedGoogle Scholar
  128. 128.
    Kisselev L, Ehrenberg M, Frolova L. Termination of translation: Interplay of mRNA, rRNAs and release factors? EMBO J 2003; 22(2):175–182PubMedGoogle Scholar
  129. 129.
    Zheng XF, Schreiber SL. Target of rapamycin proteins and their kinase activities are required for meiosis. Proc Natl Acad Sci USA 1997; 94(7):3070–3075.PubMedGoogle Scholar
  130. 130.
    Lawrence Jr JC. mTOR-dependent control of skeletal muscle protein synthesis. Int J Sport Nutr Exerc Metab 2001; 11(Suppl):117–85.Google Scholar
  131. 131.
    Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR, Genes Dev 2001; 15(7):807–26.PubMedGoogle Scholar
  132. 132.
    Denning G, Jamieson L, Maquat LE et al. Cloning of a novel phosphatidylinositol kinase-related kinase: Characterization of the human SMG-1 RNA surveillance proetin. J Biol Chem 2001; 276(25):22709–22714.PubMedGoogle Scholar
  133. 133.
    Choi KM, McMahon LP, Lawrence Jr JC. Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor. J Biol Chem 2003; 278(22):19667–19673.PubMedGoogle Scholar
  134. 134.
    Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002: 110(2):163–175.PubMedGoogle Scholar
  135. 135.
    Nojima H, Kokunaga C, Eguchi S et al. 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 2003; 278(18):15461–4.PubMedGoogle Scholar
  136. 136.
    Kim DH, Sarbassov DD, Ali SM 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.PubMedGoogle Scholar
  137. 137.
    Schalm SS, Fingar DC, Sabatini DM et al. TOS motif-mediated raator binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003; 13(10):797–806.PubMedGoogle Scholar
  138. 138.
    Hara K, Maruki Y, Long X et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110(2):177–89.PubMedGoogle Scholar
  139. 139.
    Brunn GJ, Fadden P, Haysted TA et al. The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J Biol Chem 1997; 272(51):32547–32550.PubMedGoogle Scholar
  140. 140.
    Brown EJ, Beal PA, Keith CT et al. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 1995; 377(6548):441–446.PubMedGoogle Scholar
  141. 141.
    Burnett PE, Barrow RK, Cohen NA et al. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 1998: 95(4):1432–1437.PubMedGoogle Scholar
  142. 142.
    Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol 2002; 12(8):632–639.PubMedGoogle Scholar
  143. 143.
    Tee AR, Proud CG. Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol 2002; 22(6):1674–83.PubMedGoogle Scholar
  144. 144.
    Scott PH, Lawrence Jr JC. Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes. J Biol Chem 1998; 273(51):34496–34501.PubMedGoogle Scholar
  145. 145.
    Scott PH, Brunn GJ, Kohn AD et al. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 1998; 95(13): 7772–7.PubMedGoogle Scholar
  146. 146.
    Reynolds TH, Bodine SC, Lawrence Jr JC. Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem 2002; 277(20):17657–17662.PubMedGoogle Scholar
  147. 147.
    Navé BT, Ouwens M, Withers DJ et al. Mammalian target of rapamycin is a direct target for protein kinase B: Identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999; 344(Pt 2):427–431.PubMedGoogle Scholar
  148. 148.
    Sekulic A, Hudson CC, Homme JL et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000; 60(13):3504–3513.PubMedGoogle Scholar
  149. 149.
    Brunn GJ, Hudson CC, Sekulic A et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277(5322):99–101.PubMedGoogle Scholar
  150. 150.
    McMahon LP, Choi KM, Lin TA et al. The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol Cell Biol 2002; 22(21):7428–38.PubMedGoogle Scholar
  151. 151.
    Tee AR, Fingar DC, Manning BD et al. Tuberous sclerosis complex-1 and −2 gene products function together to inhibit mammalian target of rapamycin (m TOR)-mediated downstream signaling. Proc Natl Acad Sci USA 2002; 99(22):1357–13576.Google Scholar
  152. 152.
    Manning BD, Tee AR, Logsdon MN et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10(1):151–162.PubMedGoogle Scholar
  153. 153.
    Gao X, Zhang Y, Arrazola P et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002; 4(9):699–704.PubMedGoogle Scholar
  154. 154.
    Dan HC, Sun M, Yang L et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002; 277(38):35364–35370.PubMedGoogle Scholar
  155. 155.
    Inoki K, Li Y, Zhu T et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4 (9):648–657.PubMedGoogle Scholar
  156. 156.
    Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4(9):658–665.PubMedGoogle Scholar
  157. 157.
    Cheadle JP, Reeve MP, Sampson JR et al. Molecular genetic advances in tuberous sclerosis. Hum Genet 2000; 107(2):97–114.PubMedGoogle Scholar
  158. 158.
    Garami A, Zwartkruis FJ, Nobukuni T 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):1457–1466.PubMedGoogle Scholar
  159. 159.
    Zhang Y, Gao X, Saucedo LJ et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003; 5(6):578–581.PubMedGoogle Scholar
  160. 160.
    Yamagata K, Sanders LK, Kaufmann WE et al. Rheb, a growth factor-and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem 1994; 269(23):16333–16339.PubMedGoogle Scholar
  161. 161.
    Stocker H, Radimerski T, Schindelholz B et al. Rheb is and essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003; 5(6):559–565.PubMedGoogle Scholar
  162. 162.
    Saucedo LJ, Gao X, Chiarelli DA et al. Rheb promotes cell growth as a component of the insulin/ TOR signalling network. Nat Cell Biol 2003; 5((6):566–571.Google Scholar
  163. 163.
    Fox HL, Pham PT, Kimball SR et al. Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytes. Am J Physiol 1998; 275(5 Pt 1): 1232–8.Google Scholar
  164. 164.
    Xu G, Kwon G, Marshall CA et al. Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. J Biol Chem 1998: 273(43):28178–84.PubMedGoogle Scholar
  165. 165.
    Anthony JC, Lang CH, Crozier SJ et al. Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine. Am J Physiol Endocrinol Metab 2002; 282(5):1092–101.Google Scholar
  166. 166.
    Beugnet A, Tee AR, Taylor PM et al. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J 2003; 372(Pt 2):555–66.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Joseph F. Christian
  • John C. LawrenceJr.
    • 1
  1. 1.Department of PharmacologyUniversity of Virginia Health SystemCharlottesvilleUSA

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