The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

EIF4EBP1  -  eukaryotic translation initiation factor...

Homo sapiens

Synonyms: 4E-BP1, 4EBP1, BP-1, Eukaryotic translation initiation factor 4E-binding protein 1, PHAS-I, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of EIF4EBP1


Psychiatry related information on EIF4EBP1


High impact information on EIF4EBP1


Chemical compound and disease context of EIF4EBP1


Biological context of EIF4EBP1

  • Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism [11].
  • Further investigation by altering FRAP's nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of FRAP and mitogenic stimulation of p70(s6k) activation and 4E-BP1 phosphorylation [12].
  • Our results suggest that 4E-BP1-mediated control of apoptosis occurs through qualitative rather than quantitative changes in protein synthesis, mediated by a dynamic interplay between cap-dependent and cap-independent processes [13].
  • 4E-BP1 plays key roles in cell proliferation, growth, and survival [14].
  • BACKGROUND: The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that controls cell growth and proliferation via the translation regulators eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) [15].

Anatomical context of EIF4EBP1

  • These findings show: that phosphorylation events govern the proapoptotic potency of 4E-BP1, that 4E-BP1 is proapoptotic in normal as well as transformed fibroblasts, and that malignant transformation is associated with a higher requirement for cap-dependent translation to inhibit apoptosis [13].
  • Recruitment of mRNAs to the ribosome is enhanced by phosphorylation of eIF4E, the cap-binding protein, and PHAS-I, a protein that specifically binds eIF4E [16].
  • Insulin and/or amino acids increased, and rapamycin decreased, the reactivity of all three antibodies with PHAS-I in both HEK293 cells and 3T3-L1 adipocytes [17].
  • In a first part, we show that the expression of 4E-BP1 protein and transcript decreases in hematopoietic cell lines cultivated in the presence of phorbol 12-myristate 13-acetate (PMA) [18].
  • Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle [19].

Associations of EIF4EBP1 with chemical compounds


Physical interactions of EIF4EBP1

  • Herein we demonstrate that raptor binds to p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs to be required for amino acid- and mTOR-dependent regulation of these mTOR substrates in vivo [22].
  • In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state [1].
  • Recently, amino acid sufficiency has been demonstrated to selectively regulate p70 S6 kinase (p70(s6k)) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are targeted by the anti-proliferative drug rapamycin [23].
  • Since mTOR activates both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest [24].
  • IGF-1 treatment increased the phosphorylation of eukaryotic initiation factor (eIF)-4E-binding protein 1 (4E-BP1), exclusively at Thr-36 and Thr-45 residues, and eIF-4G phosphorylation at Ser-1108 [25].

Enzymatic interactions of EIF4EBP1

  • FRAP/mTOR has been reported to phosphorylate 4E-BP1 directly in vitro [11].
  • The homology is most striking in the middle region of the protein, which contains the eIF4E binding motif and residues that are phosphorylated in 4E-BP1 [26].
  • The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression [27].

Regulatory relationships of EIF4EBP1


Other interactions of EIF4EBP1


Analytical, diagnostic and therapeutic context of EIF4EBP1

  • Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins [35].
  • We now demonstrate that CCI-779 rapidly inhibits mTOR activity, as indicated by S6 reduction and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation in two xenograft models of RMS within 24 hours of treatment [36].
  • For each individual site, we have analyzed the effects of modification on eIF4E binding using affinity chromatography and surface plasmon resonance analysis, and on the regulatory function of the 4E-BP1 protein using a yeast in vivo model system and a mammalian in vitro translation assay [37].
  • PHAS-I was also phosphorylated at a significant rate by casein kinase II and protein kinase C. To investigate sites of phosphorylation, PHAS-I was digested with collagenase and phosphopeptides were resolved by reverse phase high performance liquid chromatography [38].
  • Systemic infusion of mixed amino acids significantly stimulated the phosphorylation of 4E-BP1 (P < 0.04) and p70(S6K) (P < 0.001) and the dephosphorylation of eIF2alpha (P < 0.003) in the control group [39].


  1. Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism. Greenberg, V.L., Zimmer, S.G. Oncogene (2005) [Pubmed]
  2. Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1. Connor, J.H., Lyles, D.S. J. Virol. (2002) [Pubmed]
  3. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Liu, L., Cash, T.P., Jones, R.G., Keith, B., Thompson, C.B., Simon, M.C. Mol. Cell (2006) [Pubmed]
  4. Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus. Gingras, A.C., Svitkin, Y., Belsham, G.J., Pause, A., Sonenberg, N. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  5. Adenovirus infection inactivates the translational inhibitors 4E-BP1 and 4E-BP2. Gingras, A.C., Sonenberg, N. Virology (1997) [Pubmed]
  6. Phosphorylated 4E-BP1 is associated with poor survival in melanoma. O'Reilly, K.E., Warycha, M., Davies, M.A., Rodrik, V., Zhou, X.K., Yee, H., Polsky, D., Pavlick, A.C., Rosen, N., Bhardwaj, N., Mills, G., Osman, I. Clin. Cancer Res. (2009) [Pubmed]
  7. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. Li, X., Alafuzoff, I., Soininen, H., Winblad, B., Pei, J.J. FEBS J. (2005) [Pubmed]
  8. Small-Molecule Inhibition of the Interaction between the Translation Initiation Factors eIF4E and eIF4G. Moerke, N.J., Aktas, H., Chen, H., Cantel, S., Reibarkh, M.Y., Fahmy, A., Gross, J.D., Degterev, A., Yuan, J., Chorev, M., Halperin, J.A., Wagner, G. Cell (2007) [Pubmed]
  9. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., Yonezawa, K. Cell (2002) [Pubmed]
  10. Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells. Connolly, E., Braunstein, S., Formenti, S., Schneider, R.J. Mol. Cell. Biol. (2006) [Pubmed]
  11. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Gingras, A.C., Gygi, S.P., Raught, B., Polakiewicz, R.D., Abraham, R.T., Hoekstra, M.F., Aebersold, R., Sonenberg, N. Genes Dev. (1999) [Pubmed]
  12. Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Kim, J.E., Chen, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  13. Translational control of cell fate: availability of phosphorylation sites on translational repressor 4E-BP1 governs its proapoptotic potency. Li, S., Sonenberg, N., Gingras, A.C., Peterson, M., Avdulov, S., Polunovsky, V.A., Bitterman, P.B. Mol. Cell. Biol. (2002) [Pubmed]
  14. The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Wang, X., Li, W., Parra, J.L., Beugnet, A., Proud, C.G. Mol. Cell. Biol. (2003) [Pubmed]
  15. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Schalm, S.S., Fingar, D.C., Sabatini, D.M., Blenis, J. Curr. Biol. (2003) [Pubmed]
  16. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mèndez, R., Myers, M.G., White, M.F., Rhoads, R.E. Mol. Cell. Biol. (1996) [Pubmed]
  17. Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. Mothe-Satney, I., Brunn, G.J., McMahon, L.P., Capaldo, C.T., Abraham, R.T., Lawrence, J.C. J. Biol. Chem. (2000) [Pubmed]
  18. ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. Rolli-Derkinderen, M., Machavoine, F., Baraban, J.M., Grolleau, A., Beretta, L., Dy, M. J. Biol. Chem. (2003) [Pubmed]
  19. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. Dreyer, H.C., Fujita, S., Cadenas, J.G., Chinkes, D.L., Volpi, E., Rasmussen, B.B. J. Physiol. (Lond.) (2006) [Pubmed]
  20. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. Chung, J., Bachelder, R.E., Lipscomb, E.A., Shaw, L.M., Mercurio, A.M. J. Cell Biol. (2002) [Pubmed]
  21. Protein kinase activity of Tel1p and Mec1p, two Saccharomyces cerevisiae proteins related to the human ATM protein kinase. Mallory, J.C., Petes, T.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  22. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. Nojima, H., Tokunaga, C., Eguchi, S., Oshiro, N., Hidayat, S., Yoshino, K., Hara, K., Tanaka, N., Avruch, J., Yonezawa, K. J. Biol. Chem. (2003) [Pubmed]
  23. L-Asparaginase inhibits the rapamycin-targeted signaling pathway. Iiboshi, Y., Papst, P.J., Hunger, S.P., Terada, N. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  24. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Mita, M.M., Mita, A., Rowinsky, E.K. Cancer Biol. Ther. (2003) [Pubmed]
  25. Regulation of cap-dependent translation by insulin-like growth factor-1 in neuronal cells. Quevedo, C., Salinas, M., Alcázar, A. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  26. 4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family. Poulin, F., Gingras, A.C., Olsen, H., Chevalier, S., Sonenberg, N. J. Biol. Chem. (1998) [Pubmed]
  27. Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells. Bishop, J.D., Nien, W.L., Dauphinee, S.M., Too, C.K. J. Endocrinol. (2006) [Pubmed]
  28. Ser-64 and Ser-111 in PHAS-I are dispensable for insulin-stimulated dissociation from eIF4E. Ferguson, G., Mothe-Satney, I., Lawrence, J.C. J. Biol. Chem. (2003) [Pubmed]
  29. PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation. Lawrence, J.C., Fadden, P., Haystead, T.A., Lin, T.A. Adv. Enzyme Regul. (1997) [Pubmed]
  30. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Peterson, R.T., Desai, B.N., Hardwick, J.S., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  31. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. Herbert, T.P., Tee, A.R., Proud, C.G. J. Biol. Chem. (2002) [Pubmed]
  32. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. Haghighat, A., Mader, S., Pause, A., Sonenberg, N. EMBO J. (1995) [Pubmed]
  33. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Burnett, P.E., Barrow, R.K., Cohen, N.A., Snyder, S.H., Sabatini, D.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  34. Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1. Azar, R., Najib, S., Lahlou, H., Susini, C., Pyronnet, S. Cell. Mol. Life Sci. (2008) [Pubmed]
  35. Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. Nathan, C.A., Amirghahari, N., Abreo, F., Rong, X., Caldito, G., Jones, M.L., Zhou, H., Smith, M., Kimberly, D., Glass, J. Clin. Cancer Res. (2004) [Pubmed]
  36. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Wan, X., Shen, N., Mendoza, A., Khanna, C., Helman, L.J. Neoplasia (2006) [Pubmed]
  37. A quantitative molecular model for modulation of mammalian translation by the eIF4E-binding protein 1. Karim, M.M., Hughes, J.M., Warwicker, J., Scheper, G.C., Proud, C.G., McCarthy, J.E. J. Biol. Chem. (2001) [Pubmed]
  38. Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. Haystead, T.A., Haystead, C.M., Hu, C., Lin, T.A., Lawrence, J.C. J. Biol. Chem. (1994) [Pubmed]
  39. Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle. Liu, Z., Li, G., Kimball, S.R., Jahn, L.A., Barrett, E.J. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
WikiGenes - Universities