The Eukaroyotic mRNA Cap Binding Protein (eIF-4E): Phosphorylation and Regulation of Cell Growth

  • R. Frederickson
  • A. Lazaris-Karatzas
  • N. Sonenberg
Conference paper
Part of the NATO ASI Series book series (volume 49)


The binding of eukaryotic mRNA to ribosomes requires the participation of at least three initiation factors: eIF-4A, eIF-4B and eIF-4F, and the hydrolysis of ATP (for reviews see Rhoads, 1988; Sonenberg, 1988). A key functional element of the eukaryotic mRNA in this process is the 5′ cap structure, m7GpppN (where N is any nucleotide). This structure facilitates ribosome binding through its interaction with the 24 kDa cap binding protein, termed eIF-4E (Sonenberg et al, 1978). eIF-4E is present in the cell in a free form and in a complex (termed eIF-4F) with two other polypeptides (Tahara et al, 1981; Grifo et al, 1983; Edery et al, 1983). One of these has been identified as eIF-4A, a 50 kDa polypeptide that possesses ATP binding and single-stranded RNA dependent ATPase activities (Sarkar et al, 1985; Abramson et al, 1987), as well as helicase activity in conjunction with eIF-4B (Ray et al, 1985; Rozen et al, 1990). The second of the polypeptides in eIF-4F is a high molecular weight subunit of 220 kDa, termed p220, whose integrity is essential for eIF-4F function (Sonenberg, 1987). eIF-4F stimulates mRNA binding to the 40S ribosomal subunit by unwinding the secondary structure in the mRNA 5′ non-coding region (Ray et al, 1985; Rozen et al, 1990).


eUkaryotic Initiation Factor Eukaryotic mRNA Phosphoamino Acid High Molecular Weight Subunit Major Phosphorylation Site 
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. Abramson RD, Dever TE, Lawson TG, Ray BK, Thach RE, Merrick WC (1987) The ATP-dependent interaction of eukaryotic initiation factors with mRNA. J Biol Chem 262: 3826–3832PubMedGoogle Scholar
  2. Altmann M, Edery I, Trachsel H, Sonenberg N (1988) Site- directed mutagenesis of the tryptophan residues in yeast eukaryotic initiation factor 4E. J Biol Chem 263: 17229–17232PubMedGoogle Scholar
  3. Bonneau AM, Sonenberg N (1987) Involvement of the 24-kDa cap binding protein in regulation of protein synthesis in mitosis. J Biol Chem 262: 11134–11139PubMedGoogle Scholar
  4. Brooks RF (1977) Continuous protein synthesis is required to maintain the probability of entry into S phase. Cell 12: 311–317PubMedCrossRefGoogle Scholar
  5. Browning KS, Lax SR, Humphreys J, Ravel JM, Jobling SA, Gehrke L (1988) Evidence that the 5f untranslated leader of mRNA affects the requirement for wheat germ initiation factors 4A, 4F and 4G. J Biol Chem 263: 9630–9637PubMedGoogle Scholar
  6. Darveau A, Pelletier J, Sonenberg N (1985) Differential efficiencies of in vitro translation of mouse c-myc transcripts differing in the 5′ untranslated region. Proc Natl Acad Sci USA 82: 2315–2319PubMedCrossRefGoogle Scholar
  7. Duncan R, Milburn SC, Hershey JWB (1987) Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control: heat shock effects on eIF-4F. J Biol Chem 262: 380–388PubMedGoogle Scholar
  8. Dutta A, Stoeckle MY, Hanafusa H (1990) Serum and v-src increase the level of a CCAAT-binding factor required for transcription from a retroviral long terminal repeat. Genes Dev 4: 243–254PubMedCrossRefGoogle Scholar
  9. Edery I, Humbelin M, Darveau A, Lee KAW, Milburn S, Hershey JWB, Trachsel H, Sonenberg N (1983) Involvement of eukaryotic initiation factor 4A in the cap recognition process. J Biol Chem 258: 11398–11403PubMedGoogle Scholar
  10. Gehrke L, Auron PE, Quigley GJ, Rich A, Sonenberg N (1983) 5′ Conformation of capped alfalfa mosaic virus ribonucleic acid 4 may reflect its independence of the cap structure or of cap-binding protein for efficient translation. Biochemistry 22: 5157–5164Google Scholar
  11. Godeau F, Persson H, Gray HE, Pardee AB (1986) c-myc expression is dissociated from DNA synthesis and cell division in Xenopus oocyte and early embryonic development. EMBO J 5: 3571–3577Google Scholar
  12. Grifo JA, Tahara SM, Morgan MA, Shatkin AJ, Merrick WC (1983). New initiation factor activity required for globin mRNA translation. J Biol Chem 258: 5804–5810PubMedGoogle Scholar
  13. Hershey JWB (1989) Protein phosphorylation controls translation rates. J Biol Chem 264: 20823–20826PubMedGoogle Scholar
  14. Hershko A, Mammont P, Shields R, Tomkins GM (1971) “Pleiotropic response”. Nature New Biol 232: 206–211PubMedGoogle Scholar
  15. Hiremath LS, Webb NR, Rhoads RE (1985) Immunological detection of the messenger RNA cap-binding protein. J Biol Chem 260: 7843–7849PubMedGoogle Scholar
  16. Jagus R, Anderson WF, Safer B (1981) Initiation of mammalian protein biosynthesis. Prog Nucleic Acid Res Mol Biol 25: 127–185PubMedCrossRefGoogle Scholar
  17. Joshi-Barve S, Rychlik W, Rhoads RE (1990) Alteration of the major phosphorylation site of eukaryotic protein synthesis initiation factor 4E prevents its association with the 48S initiation complex. J Biol Chem 265: 2979–2983PubMedGoogle Scholar
  18. Kirschmeier PT, Housey GM, Johnson MD, Perkins AS, Weinstein B (1988) Construction and characterization of retroviral vector demonstrating efficient expression of cloned cDNA sequences. DNA 7: 219–225PubMedCrossRefGoogle Scholar
  19. Kmiecik TE, Shalloway D (1987) Activation and supression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell 49: 65–73PubMedCrossRefGoogle Scholar
  20. Kozma SC, Ferrari S, Thomas G (1989) Unmasking a growth factor/oncogene-activated S6 phosphorylation cascade. Cellular Signalling 1: 219–225PubMedCrossRefGoogle Scholar
  21. Krebs EG, Beavo JA (1979) Phosphorylation and dephosphorylation of enzymes. Ann Rev Biochem 48: 92 3–959Google Scholar
  22. Lazaris-Karatzas A, Montine KS, Sonenberg N (1990) Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5f cap. Nature In pressGoogle Scholar
  23. Marino MW, Pfeffer LM, Guidon PT, Donner DB (1989) Tumor necrosis factor induces phosphorylation of a 28 kDa mRNA cap-binding protein in human cervical carcinoma cells. Proc Natl Acad Sci USA 86: 8417–8421PubMedCrossRefGoogle Scholar
  24. Marth JD, Overell RW, Meier KE, Krebs EG, Perlmutter RM (1988) Translational activation of the lck proto-oncogene. Nature 332: 171–173PubMedCrossRefGoogle Scholar
  25. Morley SJ, Traugh JA (1989) Phorbol esters stimulate phosphorylation of eukaryotic initiation factors 3,4B and 4F. J Biol Chem 264: 2401–2404PubMedGoogle Scholar
  26. Morley SJ, Traugh JA (1990) 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 In pressGoogle Scholar
  27. Rao CD, Pech M, Robbins KC, Aaronson SA (1986) The 5′ untranslated sequence of the c-sis/platelet-derived growth factor 2 transcript is a potent translational inhibitor. Mol Cell Biol 8: 284–292Google Scholar
  28. Ray BK, Lawson TG, Kramer JC, Cladaras MH, Grifo JA, Abramson RD, Merrick WC, Thach RE (1985) ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors. J Biol Chem 260: 7651–6758PubMedGoogle Scholar
  29. Rhoads RE (1988) Cap recognition and the entry of mRNA into the protein synthesis initiation cycle. Trends Biochem Sci 13: 52–56PubMedCrossRefGoogle Scholar
  30. Rozen F, Edery I, Meerovitch K, Dever TE, Merrick WC, Sonenberg N (1990) Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol Cell Biol 10: 1134–1144PubMedGoogle Scholar
  31. Rychlik W, Gardner PR, Vanaman TC, Rhoads RC (1986) Structural analysis of the messenger RNA cap-binding Protein: presence of phosphate, sulfhydryl, and disulfide groups. J Biol Chem 261: 71–75PubMedGoogle Scholar
  32. Rychlik W, Russ MA, Rhoads RE (1987) Phosphorylation site of eukaryotic initiation factor 4E. J Biol Chem 262: 10434–10437PubMedGoogle Scholar
  33. Sarkar G, Edery I, Gallo R, Sonenberg N (1984). Preferential stimulation of rabbit a globin mRNA translation by a cap binding protein complex. Biochim Biophys Acta 783: 122–129PubMedGoogle Scholar
  34. Sarkar G, Edery I, Sonenberg N (1985) Photoaffinity labeling of the cap-binding protein complex with ATP/dATP. J Biol Chem 260: 13831–13837PubMedGoogle Scholar
  35. Sonenberg N (1987) Regulation of translation by poliovirus. Adv Virus Res 33: 175–204PubMedCrossRefGoogle Scholar
  36. Sonenberg N (1988) Cap binding proteins of eukaryotic messenger RNA: Functions in initiation and control of translation. Prog Nucl Acid Res Mol Biol 35: 174–207Google Scholar
  37. Sonenberg N, Morgan MA, Merrick WC, Shatkin AJ (1978) A polypeptide in eukaryotic initiation factors that crosslinks specifically to the 51-terminal cap in mRNA. Proc Natl Acad Sci USA 75: 4843–4847PubMedCrossRefGoogle Scholar
  38. Sonenberg N, Trachsel H, Hecht S, Shatkin AJ (1980) Differential stimulation of capped mRNA translation in vitro by cap binding protein. Nature 285: 331–333PubMedCrossRefGoogle Scholar
  39. Tahara S, Morgan MA, Shatkin AJ (1981) Two forms of purified m7G-cap binding proteins with different effects on capped mRNA translation in extracts of uninfected and polio- virus-infected HeLa cells. J Biol Chem 256: 7691–7694PubMedGoogle Scholar
  40. Veillette A, Horak ID, Bolen JB (1988) Post-translational alterations of the tyrosine kinase p56lck in response to activators of protein kinase C. Oncogene Res 2: 385–401PubMedGoogle Scholar
  41. Veillette A, Horak ID, Horak EM, Bookman MA, Bolen JB (1988) Alterations of the lymphocyte-specific protein tyrosine kinase during T-cell activation. Mol Cell Biol 8: 4353–4361PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • R. Frederickson
    • 1
  • A. Lazaris-Karatzas
    • 1
  • N. Sonenberg
    • 1
  1. 1.Department of BiochemistryMcGill UniversityMontreal, QuebecCanada

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