EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)

2012-03-01   Michael Clemens , Mark Coldwell , Androulla Elia 

Dept of Chemistry, Biochemistry, School of Life Sciences, University of Sussex, Division of Basic Medical Sciences, St Georges, University of London, United Kingdom (MCl); School of Biological Sciences, University of Southampton, United Kingdom (MCo)





The EIF4EBP1 gene codes for 4E-BP1, one member of a family of small proteins that act as repressors of translation. The gene is 29,86 kb in length and contains three exons, comprising nucleotides 1-217, 218-397 and 398-859 of the mature mRNA.


EIF4EBP1 transcription is positively regulated by ATF4 in response to cell stress (Yamaguchi et al., 2008) and by Smad4 in response to transforming growth factor β (Azar et al., 2009). There is evidence that activity of the phosphatidylinositol 3-kinase (PI3K) and MAP kinase pathways can negatively regulate the transcription of EIF4EBP1 (Azar et al., 2008), possibly via the transcription factor Egr-1 (Rolli-Derkinderen et al., 2003).


Two pseudogenes with homology to 4E-BP1 exist in the human genome, located at 14q11.2 (LOC768328) and 22q12 (EIF4EBP1P), with the latter pseudogene present on the antisense strand of the gene locus encoding chromodomain helicase DNA binding protein 8 (CHD8).


Atlas Image
The diagram illustrates key regulatory features of the human 4E-BP1 protein, including the RAIP and TOS motifs that are important for the phosphorylation of the protein at Thr37, Thr46, Ser65, Thr70 and Ser101 by the Raptor/mTOR complex (Eguchi et al., 2006; Lee et al., 2008). Additional phosphorylation sites have been identified at Ser83 and Ser112. The region required for binding of 4E-BP1 to initiation factor eIF4E and a site of cleavage of the protein by caspases in apoptotic cells are also shown (diagram adapted from an original prepared by Dr C. Constantinou).


Human 4E-BP1 is a 118 amino acid protein (119 amino acids including the initiating methionine) and is encoded by an mRNA containing 877 nucleotides (including a short poly(A) tail). The mRNA has a 72 nucleotide 5 untranslated region and a 448 nucleotide 3 untranslated region. The coding region comprises nucleotides 73-429. The protein can be reversibly phosphorylated at Thr37, Thr46, Ser65, Thr70, Ser83, Ser101 and Ser112 in response to a variety of physiological stimuli. The key enzyme involved in these phosphorylations is the protein kinase mTOR, but other kinases may also be involved (Yonezawa et al., 2004).


4E-BP1 is ubiquitously expressed, although its presence is not essential to the viability of cells or the organism as a whole (Le Bacquer et al., 2007). The protein is stable (half-life more than 16h) but can be ubiquitinated and targeted for degradation by a mechanism that responds to its state of phosphorylation (Elia et al., 2008). The level of expression and state of phosphorylation of the protein may influence cellular phenotype, with high levels of phosphorylated 4E-BP1 in breast, ovary, and prostate tumours being associated with malignant progression and an adverse prognosis (Armengol et al., 2007). Conversely, hypophosphorylated 4E-BP1 may have an anti-oncogenic role due to its inhibitory effect on eIF4E and its potential pro-apoptotic properties (Li et al., 2002).


4E-BP1 is present in both cytoplasm and nucleus. The hypophosphorylated protein in the latter compartment can sequester eIF4E within the nucleus under conditions of physiological stress (Rong et al., 2008).


The members of the 4E-BP family of proteins act by binding to the mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E), in competition with another initiation factor, eIF4G, that is essential for polypeptide chain initiation. Thus the availability of eIF4E for translation of cap-dependent mRNAs is limited by the extent to which this factor is sequestered by the 4E-BPs.
4E-BP1 is reversibly phosphorylated at multiple sites (see diagram above), in response to several physiological signals that promote translation (Proud, 2004; Wang et al., 2005; Proud, 2006). Such phosphorylations lower the affinity of 4E-BP1 for eIF4E and result in the dissociation of the two proteins, thereby enhancing the level of active eIF4E and promoting the translation of capped mRNAs, most likely in a selective manner (Averous et al., 2008). Conversely, physiological stresses and other conditions that inhibit translation - e.g. exposure of cells to cytokines of the TNFalpha family (Lang et al., 2007; Jeffrey et al., 2006) or activation of the tumour suppressor protein p53 (Tilleray et al., 2006; Constantinou and Clemens, 2007) - cause dephosphorylation of 4E-BP1 and increase binding of the latter to eIF4E. 4E-BP1 is also susceptible to other post-translational modifications, notably specific proteolytic cleavages (Tee and Proud, 2002; Constantinou et al., 2008) and phosphorylation-dependent ubiquitination (Elia et al., 2008).
There is good evidence for involvement of 4E-BP1 in malignant transformation. The protein can negatively regulate cell growth, block cell cycle progression and revert the transformed phenotype of cells over-expressing eIF4E (Rousseau et al., 1996; Jiang et al., 2003; Barnhart et al., 2008). It has been shown that 4E-BP1 is a key regulator of the oncogenic Akt (protein kinase B) and ERK (extracellular-regulated kinase) signalling pathways and it integrates the function of these pathways in tumours (She et al., 2010). Consistent with this, high levels of phosphorylated (inactive) 4E-BP1 indicate poor prognosis in some cancer patients (Castellvi et al., 2006; Frederick et al., 2011).
Although 4E-BP1 is not essential to viability the protein (together with its homologue 4E-BP2) is important for regulation of adipogenesis and insulin resistance (Le Bacquer et al., 2007). The 4E-BPs have also been reported to play a role in myelopoiesis (Olson et al., 2009). There is a major role for 4E-BP1 in the responses of cells to hypoxia, which promotes dephosphorylation of the protein (Koritzinsky et al., 2006; Connolly et al., 2006 ; Barnhart et al., 2008). It is likely that this response implements hypoxia-induced changes in gene expression at the translational level (Magagnin et al., 2008; Barnhart et al., 2008).


4E-BP1 was identified alongside another member of the eIF4E-binding protein family designated 4E-BP2 (Pause et al., 1994). A further homologue has also been identified, 4E-BP3 (Poulin et al., 1998), and these proteins respectively share 55,7% identity (82,0% similarity) and 50,8% identity (66,9% similarity) with 4E-BP1. All share the central eIF4E binding motif and are capable of competing with the eIF4G proteins for binding to eIF4E.
Atlas Image
CLUSTAL 2.0.10 multiple sequence alignment.



No mutations have been identified.

Implicated in

Entity name
Breast cancer
Elevated expression of eIF4E in human cancer often correlates with poor prognosis (Culjkovic et al., 2007). Likewise, expression of phosphorylated 4E-BP1 (which is inactive as an inhibitor of eIF4E) is associated with malignant progression and an adverse prognosis in breast, ovary, and prostate tumours (Armengol et al., 2007).
Because 4E-BP1 is an antagonist of the oncogenic initiation factor eIF4E (Avdulov et al., 2004), it might be anticipated that 4E-BP1 could function as a pro-apoptotic tumour suppressor protein. However it has been reported that a majority of large advanced breast cancers overexpress 4E-BP1 (Braunstein et al., 2007). The latter may contribute to tumourigenesis (in combination with overexpressed eIF4G) by promoting a hypoxia-activated switch in selective mRNA translation that enhances angiogenesis and tumour cell growth and survival.



Although no breakpoints within the 4E-BP1 gene locus have been identified, the chromosomal region containing 4E-BP1 (8p11-12) is frequently rearranged in breast carcinomas. However, microarray profiling of the genes within these regions in breast tumours and cell lines shows that rearrangements of the chromosome do not correlate with significantly changed 4E-BP1 mRNA expression (Gelsi-Boyer et al., 2005).


Pubmed IDLast YearTitleAuthors
1769975720074E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications.Armengol G et al
151932582004Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells.Avdulov S et al
177244762008Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1.Averous J et al
1983445620094E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation.Azar R et al
188103192008Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.Azar R et al
187087532008Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival.Barnhart BC et al
179967132007A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer.Braunstein S et al
169837022006Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer.Castellvi J et al
166484882006Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells.Connolly E et al
180210752008Activation of p53 stimulates proteasome-dependent truncation of eIF4E-binding protein 1 (4E-BP1).Constantinou C et al
172451132007Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E.Culjkovic B et al
168241952006Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size.Eguchi S et al
176530842008Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1.Elia A et al
212817882011Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.Frederick MJ et al
163805032005Comprehensive profiling of 8p11-12 amplification in breast cancer.Gelsi-Boyer V et al
169115202006Interferon-alpha induces sensitization of cells to inhibition of protein synthesis by tumour necrosis factor-related apoptosis-inducing ligand.Jeffrey IW et al
126335042003Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells.Jiang H et al
164678442006Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control.Koritzinsky M et al
175050522007Regulation of muscle protein synthesis during sepsis and inflammation.Lang CH et al
172735562007Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2.Le Bacquer O et al
183843762008Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1.Lee VH et al
119099772002Translational control of cell fate: availability of phosphorylation sites on translational repressor 4E-BP1 governs its proapoptotic potency.Li S et al
182196972008The mTOR target 4E-BP1 contributes to differential protein expression during normoxia and hypoxia through changes in mRNA translation efficiency.Magagnin MG et al
191757922009Impaired myelopoiesis in mice lacking the repressors of translation initiation, 4E-BP1 and 4E-BP2.Olson KE et al
79358361994Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function.Pause A et al
959375019984E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family.Poulin F et al
165450792006Regulation of protein synthesis by insulin.Proud CG et al
126184312003ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1.Rolli-Derkinderen M et al
185155452008Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs.Rong L et al
89570831996The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth.Rousseau D et al
2060935120104E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors.She QB et al
118650472002Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif.Tee AR et al
165041792006Regulation of protein synthesis by inducible wild-type p53 in human lung carcinoma cells.Tilleray V et al
157676632005Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins.Wang X et al
183160322008ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress.Yamaguchi S et al
145609632004Kinase activities associated with mTOR.Yonezawa K et al

Other Information

Locus ID:

NCBI: 1978
MIM: 602223
HGNC: 3288
Ensembl: ENSG00000187840


dbSNP: 1978
ClinVar: 1978
TCGA: ENSG00000187840


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
ErbB signaling pathwayKEGGko04012
mTOR signaling pathwayKEGGko04150
Insulin signaling pathwayKEGGko04910
Acute myeloid leukemiaKEGGko05221
ErbB signaling pathwayKEGGhsa04012
mTOR signaling pathwayKEGGhsa04150
Insulin signaling pathwayKEGGhsa04910
Acute myeloid leukemiaKEGGhsa05221
RNA transportKEGGko03013
RNA transportKEGGhsa03013
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
HIF-1 signaling pathwayKEGGhsa04066
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
Metabolism of proteinsREACTOMER-HSA-392499
Eukaryotic Translation InitiationREACTOMER-HSA-72613
Cap-dependent Translation InitiationREACTOMER-HSA-72737
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43SREACTOMER-HSA-72662
Signal TransductionREACTOMER-HSA-162582
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
PKB-mediated eventsREACTOMER-HSA-109703
mTOR signallingREACTOMER-HSA-165159
mTORC1-mediated signallingREACTOMER-HSA-166208
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Gene ExpressionREACTOMER-HSA-74160
Longevity regulating pathwayKEGGhsa04211
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
120800862002Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.384
128209602003Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.349
122711412002Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.243
242066642013mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation.238
126046102003The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.208
187019202008Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila.193
2060935120104E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors.167
168734122006Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle.158
218413102011Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator.135
184398972008The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1.113


Michael Clemens ; Mark Coldwell ; Androulla Elia

EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version: http://atlasgeneticsoncology.org/gene/40432/eif4ebp1-(eukaryotic-translation-initiation-factor-4e-binding-protein-1)

Historical Card

2009-02-01 EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) by  Michael Clemens,Mark Coldwell 

Dept of Chemistry, Biochemistry, School of Life Sciences, University of Sussex, Division of Basic Medical Sciences, St Georges, University of London, United Kingdom (MCl); School of Biological Sciences, University of Southampton, United Kingdom (MCo)