Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4E
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:98,879,276-98,929,133 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q23 | {Autism, susceptibility to, 19} | 615091 | 3 |
All eukaryotic cellular mRNAs are blocked at their 5-prime ends with the 7-methylguanosine cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. EIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs. It is a 24-kD polypeptide that exists as both a free form and as part of a multiprotein complex termed EIF4F. The EIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis. The other subunits of EIF4F are a 50-kD polypeptide, termed EIF4A (see 601102), that possesses ATPase and RNA helicase activities, and a 220-kD polypeptide, EIF4G (600495) (summary by Rychlik et al., 1987).
Rychlik et al. (1987) cloned and sequenced EIF4E from human erythrocytes.
Pause et al. (1994) identified 2 homologous proteins, EIF4EBP1 (602223) and EIF4EBP2 (602224), that bind to EIF4E and may regulate its activity.
Jones et al. (1997) stated that EIF4E is the rate-limiting component in protein synthesis and may play a role in growth regulation. The overexpression of EIF4E can cause malignant transformation.
Waskiewicz et al. (1997) identified EIF4E as a potential physiologic substrate for Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069) in mouse. Using coimmunoprecipitation experiments, Pyronnet et al. (1999) demonstrated that MNK1 interacts with the EIF4F complex via its interaction with the C-terminal region of EIF4G, not through a direct interaction with EIF4E. An EIF4E mutant lacking EIF4G-binding capability was poorly phosphorylated in cells. Pyronnet et al. (1999) hypothesized that EIF4G provides a docking site for MNK1 to phosphorylate EIF4E.
In mammals, MTOR (601231) cooperates with PI3K (see 171834)-dependent effectors in a biochemical signaling pathway to regulate the size of proliferating cells. Fingar et al. (2002) presented evidence that rat S6k1 alpha-II (608938), Eif4e, and Eif4ebp1 mediate Mtor-dependent cell size control.
Using a murine lymphoma model, Wendel et al. (2004) demonstrated that Akt (164730) promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signaling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. The translational regulator Eif4e, which acts downstream of Akt and mTOR, recapitulated the action of Akt in tumorigenesis and drug resistance but was unable to confer sensitivity to rapamycin and chemotherapy. Wendel et al. (2004) concluded that their results established Akt signaling through mTOR and Eif4e as an important mechanism of oncogenesis and drug resistance in vivo and revealed how targeting apoptotic programs can restore drug sensitivity in a genotype-dependent manner.
Syntichaki et al. (2007) showed that loss of a specific eIF4E isoform, Ife2, that functions in somatic tissues reduces global protein synthesis, protects from oxidative stress, and extends life span in Caenorhabditis elegans. Life span extension was independent of the forkhead transcription factor Daf16 (see 136533), which mediates the effects of the insulin-like signaling pathway on aging. Furthermore, Ife2 deficiency further extended the life span of long-lived 'age' and 'daf' nematode mutants. Similarly, lack of Ife2 enhanced the long-lived phenotype of 'clk' and dietary-restricted 'eat' mutant animals. Knockdown of target of rapamycin (Tor; see 601231), a phosphatidylinositol kinase-related kinase that controls protein synthesis in response to nutrient cues, further increased the longevity of Ife2 mutants. Thus, Syntichaki et al. (2007) concluded that signaling via eIF4E in the soma influences aging in C. elegans.
Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK (176872), and anti-BRAF plus anti-MEK drug combinations in BRAF(V600) (164757.0001)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1; or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.
Scaffold protein eIF4G1 in the eIF4F complex binds to the m7G-cap-binding protein eIF4E and the RNA helicase eIF4A. EIF4G1 can also directly interact with eIF1 (619901), and both eIF1 and eIF4G1 are required for scanning and AUG selection in mammalian translation. Using immunoprecipitation analysis, Haimov et al. (2018) showed that interaction of eIF4E and eIF1 with eIF4G1 was mutually exclusive, as eIF4G1 coprecipitated either with eIF4E or eIF1, but not both. Mutation analysis showed that the eIF1 surface residues K109 and H111 were important for interaction with eIF4G1. Knockdown analysis in HEK293T cells revealed that eIF1-eIF4G1 interaction was required for leaky scanning, in particular for avoiding m7G-cap-proximal AUG. EIF4E-eIF4G1 antagonized scanning promoted by eIF1-eIF4G1, and eIF4G1 needed to dissociate itself from eIF4E and engage with eIF1 to promote scanning activity. Mapping the binding sites on eIF4G1 identified a binding site for eIF1. However, in addition to the major eIF4E-binding site on eIF4G1, eIF4E also indirectly bound to the eIF1-binding site, and eIF1 and eIF4E competed for the shared binding site on eIF4G1.
Gross et al. (2003) reported the solution structure of the complex between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids 393 to 490). Binding between these proteins triggered folding of the N terminus of Eif4e with concomitant folding of Eif4g through a mutually induced fit mechanism. Protein binding altered the conformation and/or the stability of the cap binding slot, resulting in enhanced association of Eif4e with the cap structure. Dissociation of the ternary complex was slow, and the N terminus of Eif4e was required for these effects. Yeast strains harboring mutants of Eif4e lacking key N-terminal residues showed impaired growth, decreased polysome content, and reduced interaction between Eif4e and Eif4g.
To map the human gene(s) for EIF4E, Pelletier et al. (1991) used species-specific PCR DNA prepared from human/rodent somatic cell hybrids. They showed that one of the human EIF4E genes (designated EIF4EL1), probably the functional one, is located on 4p15-qter. A second EIF4E gene, EIF4EL2, was located on human chromosome 20 by Southern blot analysis of mapping panels established from human/rodent somatic cell hybrids. The authors stated that this gene may represent a pseudogene.
As a critical component of the cap binding protein, EIF4E plays an important role in growth regulation. There is evidence that it can function as an oncogene. Jones et al. (1996) cloned genomic segments from human DNA that encoded the promoter and first exon of human EIF4E. Previous mapping studies localizing the EIF4E gene to chromosome 4 were complicated by cross hybridization with multiple pseudogenes. On the other hand, probes corresponding to the cloned promoter region of the EIF4E gene detected unique bands in genomic Southern hybridizations. Using oligonucleotide primers specific for the promoter region, Jones et al. (1997) PCR-amplified the human gene in a chromosome 4-specific human/rodent somatic cell panel. This panel mapped single-copy genomic sequences for EIF4E in the region 4q21-q25.
Dorfman et al. (1991) determined that an EIF4E gene is located on mouse chromosome 12. The gene mapped to mouse chromosome 12 is perhaps unlikely to be the homolog of the gene that maps to human chromosome 4 in light of other information on the homologies of synteny between the 2 species. Jones et al. (1997) used PCR analysis of human-rodent somatic cell panels to map the EIF4E gene to human chromosome 4q21-q25. They noted that the mapping of this gene has been complicated by ambiguities associated with pseudogenes; Jones et al. (1997) therefore used sequences from the promoter region.
Following the identification in a boy with classic autism (AUTS19; 615091) of a de novo balanced translocation in which one of the breakpoints occurred within a proposed alternative transcript of EIF4E, Neves-Pereira et al. (2009) screened 120 multiplex families with 2 autistic sibs for mutation in EIF4E. They identified an identical single-base insertion in the promoter region (133440.0001) in 2 unrelated autistic sib pairs and in their respective fathers. The variant was not found in 1,020 anonymous control samples. Electrophoretic mobility shift assays and reporter gene studies showed that this mutation enhances binding of a nuclear factor and EIF4E promoter activity.
Ruggero et al. (2004) generated transgenic mice that overexpressed Eif4e and observed a marked increase in tumorigenesis in the mice when compared with their wildtype littermates. When these transgenic mice were intercrossed with a strain overexpressing the Myc oncogene (MYC; 190080), the double-transgenic offspring developed lymphoma at a markedly accelerated rate. In double-transgenic B cells, the ability of Myc to induce apoptosis was markedly reduced and Eif4e's induction of cellular senescence in vivo in splenic B cells was completely abrogated. Ruggero et al. (2004) suggested that activation of EIF4E may be a key event in oncogenic transformation by phosphoinositide-3 kinase (see 171833) and Akt.
Gkogkas et al. (2013) demonstrated that knockout of the eukaryotic translation initiation factor 4E-binding protein-2 (EIF4EBP2; 602224) (an EIF4E repressor downstream of MTOR, 601231), or EIF4E overexpression leads to increased translation of neuroligins, postsynaptic proteins that are causally linked to autism spectrum disorders (ASDs). Mice with knockout of Eif4ebp2 exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors (i.e., social interaction deficits, altered communication, and repetitive/stereotyped behaviors). Pharmacologic inhibition of Eif4e activity or normalization of neuroligin-1 (600568), but not neuroligin-2 (606479), protein levels restored the normal excitation/inhibition ratio and rectified the social behavior deficits. Thus, Gkogkas et al. (2013) concluded that translational control by EIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.
Santini et al. (2013) found that genetically increasing the levels of Eif4e in mice results in exaggerated cap-dependent translation and aberrant behaviors reminiscent of autism, including repetitive and perseverative behaviors and social interaction deficits. Moreover, these autistic-like behaviors are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum, and hippocampus. The autistic-like behaviors displayed by the Eif4e transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Santini et al. (2013) concluded that their findings demonstrated a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction, and aberrant behaviors associated with autism.
In 2 probands with autism (AUTS19; 615091) from unrelated families, Neves-Pereira et al. (2009) detected the same single-basepair insertion of a C nucleotide at position -25 in the promoter region of the EIF4E gene. Each proband had an autistic sib, in whom the mutation was found; the mutation was also found in the fathers of all 4 affected children, but was not present in 2,040 control chromosomes. The insertion extended a run of 7 C nucleotides to 8 within the EIF4E basal promoter element (4EBE) that binds HNRNPK (600712). Neves-Pereira et al. (2009) performed electrophoretic mobility shift assays and reporter gene studies and showed that this mutation enhances binding of a nuclear factor, probably HNRNPK, and EIF4E promoter activity. Neves-Pereira et al. (2009) suggested that pharmacologic manipulation of EIF4E may provide therapeutic benefit for those with autism caused by disturbance of the converging pathways controlling EIF4E activity.
Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 513: 105-109, 2014. [PubMed: 25079330] [Full Text: https://doi.org/10.1038/nature13572]
Dorfman, J., Lazaris-Karatzas, A., Malo, D., Sonenberg, N., Gros, P. Chromosomal assignment of one of the mammalian translation initiation factor eIF-4E genes. Genomics 9: 785-788, 1991. [PubMed: 1674733] [Full Text: https://doi.org/10.1016/0888-7543(91)90379-s]
Fingar, D. C., Salama, S., Tsou, C., Harlow, E., Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002. [PubMed: 12080086] [Full Text: https://doi.org/10.1101/gad.995802]
Gkogkas, C. G., Khoutorsky A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., Major, F., Lasko, P., Ruggero, D., Nader, K., Lacaille, J.-C., Sonenberg, N. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493: 371-377, 2013. [PubMed: 23172145] [Full Text: https://doi.org/10.1038/nature11628]
Gross, J. D., Moerke, N. J., von der Haar, T., Lugovskoy, A. A., Sachs, A. B., McCarthy, J. E. G., Wagner, G. Ribosome loading onto the mRNA cap is driven by conformational coupling between eIF4G and eIF4E. Cell 115: 739-750, 2003. [PubMed: 14675538] [Full Text: https://doi.org/10.1016/s0092-8674(03)00975-9]
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Pause, A., Belsham, G. J., Gingras, A.-C., Donze, O., Lin, T.-A., Lawrence, J. C., Jr., Sonenberg, N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5-prime-cap function. Nature 371: 762-767, 1994. [PubMed: 7935836] [Full Text: https://doi.org/10.1038/371762a0]
Pelletier, J., Brook, J. D., Housman, D. E. Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20. Genomics 10: 1079-1082, 1991. [PubMed: 1916814] [Full Text: https://doi.org/10.1016/0888-7543(91)90203-q]
Pyronnet, S., Imataka, H., Gingras, A.-C., Fukunaga, R., Hunter, T., Sonenberg, N. Human eukaryotic translation initiation factor 4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279, 1999. [PubMed: 9878069] [Full Text: https://doi.org/10.1093/emboj/18.1.270]
Ruggero, D., Montanaro, L., Ma, L., Xu, W., Londei, P., Cordon-Cardo, C., Pandolfi, P. P. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10: 484-486, 2004. [PubMed: 15098029] [Full Text: https://doi.org/10.1038/nm1042]
Rychlik, W., Domier, L. L., Gardner, P. R., Hellmann, G. M., Rhoads, R. E. Amino acid sequence of the mRNA cap-binding protein from human tissues. Proc. Nat. Acad. Sci. 84: 945-949, 1987. Note: Erratum: Proc. Nat. Acad. Sci. 89: 1148 only, 1992. [PubMed: 3469651] [Full Text: https://doi.org/10.1073/pnas.84.4.945]
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Syntichaki, P., Troulinaki, K., Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445: 922-926, 2007. [PubMed: 17277769] [Full Text: https://doi.org/10.1038/nature05603]
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Wendel, H.-G., de Stanchina, E., Fridman, J. S., Malina, A., Ray, S., Kogan, S., Cordon-Cardo, C., Pelletier, J., Lowe, S. W. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: 332-337, 2004. [PubMed: 15029198] [Full Text: https://doi.org/10.1038/nature02369]