eIF4E

{{Short description|Protein-coding gene in the species Homo sapiens}}

Overview

Eukaryotic translation initiation factor 4E, also known as eIF4E, is a pivotal protein that supports fundamental biological processes like translation initiation and impacts various disease states. Its regulation and function make it a rich target for therapeutic interventions, especially in conditions where protein synthesis is dysregulated. This protein in humans is encoded by the EIF4E gene.{{cite journal | vauthors = Pelletier J, Brook JD, Housman DE | title = Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20 | journal = Genomics | volume = 10 | issue = 4 | pages = 1079–1082 | date = August 1991 | pmid = 1916814 | doi = 10.1016/0888-7543(91)90203-Q }}{{cite journal | vauthors = Jones RM, MacDonald ME, Branda J, Altherr MR, Louis DN, Schmidt EV | title = Assignment of the human gene encoding eukaryotic initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4 | journal = Somatic Cell and Molecular Genetics | volume = 23 | issue = 3 | pages = 221–223 | date = May 1997 | pmid = 9330633 | doi = 10.1007/BF02721373 | s2cid = 10683455 }}

Discovery

eIF4E was discovered as a cytoplasmic cap binding protein functioning in translation by Witold Filipowicz at al.{{Cite journal |last=Filipowicz |first=W |last2=Furuichi |first2=Y |last3=Sierra |first3=J M |last4=Muthukrishnan |first4=S |last5=Shatkin |first5=A J |last6=Ochoa |first6=S |date=15 May 1976 |title=A protein binding the methylated 5'-terminal sequence, m7GpppN, of eukaryotic messenger RNA |url=https://doi.org/10.1073/pnas.73.5.1559 |journal=PNAS |volume=73 |issue=5 |pages=1559-1563}}.in 1976. Two years later, in 1978, Sonenberg et al.{{Cite journal |last=Sonenberg |first=N |last2=Morgan |first2=M A |last3=Merrick |first3=W C |last4=Shatkin |first4=A J |date=18 October 1978 |title=A polypeptide in eukaryotic initiation factors that crosslinks specifically to the 5'-terminal cap in mRNA |url=https://doi.org/10.1073/pnas.75.10.4843 |journal=PNAS |volume=75 |issue=10 |pages=4843-4847}} confirmed Filipowicz et al.’s findings by repeating exactly the same experiments and adding a crosslinking chemical to increase the stability of the mRNA-protein complex. This has been confirmed by numerous scientists in their published articles such as Katherine L. B. Borden {{Cite journal |last=Borden |first=Katherine L. B. |date=10 Aug 2016 |title=The eukaryotic translation initiation factor eIF4E wears a “cap” for many occasions |url=https://doi.org/10.1080/21690731.2016.1220899 |journal=Translation |volume=4 |issue=2 |pages=e1220899}} , Michael J. Osborne and Katherine L.B. Borden {{Cite journal |last=Osborne |first=Michael J. |last2=Borden |first2=Katherine L. B. |date=15 December 2014 |title=The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled |url=https://doi.org/10.1111/imr.12240 |journal=Immunol Rev. |volume=263 |issue=1 |pages=210-223}} , Davis Joseph {{Cite journal |last=Joseph |first=Davis |date=15 November 2024 |title=The Fundamental Neurobiological Mechanism of Oxidative Stress-Related 4E-BP2 Protein Deamidation |url=https://doi.org/10.3390/ijms252212268 |journal=Int. J. Mol. Sci. |volume=25 |issue=22 |pages=12268}} and Davis Joseph {{Cite journal |last=Joseph |first=Davis |date=27 April 2025 |title=The Unified Theory of Neurodegeneration Pathogenesis Based on Axon Deamidation |url=https://doi.org/10.3390/ijms26094143 |journal=Int. J. Mol. Sci. |volume=26 |issue=9 |pages=4143}} .

Structure

Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine five-prime cap structure, m⁷GpppX (where X is any nucleotide). eIF4E is a eukaryotic translation initiation factor that binds specifically to this cap structure. It is a 24-kD polypeptide that exists both in a free form and as part of the eIF4F pre-initiation complex.{{cite journal | vauthors = Sonenberg N, Rupprecht KM, Hecht SM, Shatkin AJ | title = Eukaryotic mRNA cap binding protein: purification by affinity chromatography on sepharose-coupled m7GDP. | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 76 | issue = 9 | pages = 4345–4349 | date = September 1979 | pmid = 291969 | pmc = 411571 | doi = 10.1073/pnas.76.9.4345 | bibcode = 1979PNAS...76.4345S | doi-access = free }}

The other subunits of eIF4F are a 47-kD polypeptide, termed eIF4A,{{cite journal | vauthors = Hutchins AP, Roberts GR, Lloyd CW, Doonan JH | title = In vivo interaction between CDKA and eIF4A: a possible mechanism linking translation and cell proliferation | journal = FEBS Letters | volume = 556 | issue = 1–3 | pages = 91–94 | date = Jan 2004 | pmid = 14706832 | doi = 10.1016/S0014-5793(03)01382-6 | s2cid = 35343626 | doi-access = free | bibcode = 2004FEBSL.556...91H }} that possesses ATPase and RNA helicase activities, and a 220-kD scaffolding polypeptide, eIF4G.{{cite journal | vauthors = Hsieh AC, Ruggero D | title = Targeting Eukaryotic Translation Initiation Factor 4E (eIF4E) in Cancer | journal = Clinical Cancer Research | volume = 16 | issue = 20 | pages = 4914–4920 | date = 11 August 2010 | pmid = 20702611 | pmc = 7539621 | doi = 10.1158/1078-0432.CCR-10-0433 | doi-access = free }}{{cite journal | vauthors = Rychlik W, Domier LL, Gardner PR, Hellmann GM, Rhoads RE | title = Amino acid sequence of the mRNA cap-binding protein from human tissues | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 4 | pages = 945–949 | date = February 1987 | pmid = 3469651 | pmc = 304336 | doi = 10.1073/pnas.84.4.945 | bibcode = 1987PNAS...84..945R | doi-access = free }}{{cite web | title = Entrez Gene: eIF4E Eukaryotic translation initiation factor 4E | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1977 }}

eIF4E is found in the nucleus of many mammalian cell types as well as in other species including yeast, drosophila and humans.{{Cite journal | vauthors = Lejbkowicz F, Goyer C, Darveau A, Neron S, Lemieux R, Sonenberg N | title = A fraction of the mRNA 5' cap-binding protein, eukaryotic initiation factor 4E, localizes to the nucleus. | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 20 | pages = 9612–9616 | date = 1992-10-15 | pmid = 1384058 | pmc = 50182 | doi = 10.1073/pnas.89.20.9612 | language = en | issn = 0027-8424 | bibcode = 1992PNAS...89.9612L | doi-access = free }}{{Cite journal | vauthors = Dostie J, Lejbkowicz F, Sonenberg N | title = Nuclear Eukaryotic Initiation Factor 4e (Eif4e) Colocalizes with Splicing Factors in Speckles | journal = The Journal of Cell Biology | volume = 148 | issue = 2 | pages = 239–247 | date = 2000-01-24 | pmid = 10648556 | pmc = 2174286 | doi = 10.1083/jcb.148.2.239 | url = https://rupress.org/jcb/article/148/2/239/20425/Nuclear-Eukaryotic-Initiation-Factor-4e-Eif4e | language = en | issn = 0021-9525 }} eIF4E is found in nuclear bodies, some of which colocalize with PML nuclear bodies, and it also appears diffusely in the nucleoplasm.{{Cite journal | vauthors = Topisirovic I, Capili AD, Borden KL | title = Gamma Interferon and Cadmium Treatments Modulate Eukaryotic Initiation Factor 4E-Dependent mRNA Transport of Cyclin D1 in a PML-Dependent Manner | journal = Molecular and Cellular Biology | volume = 22 | issue = 17 | pages = 6183–6198 | date = 2002-09-01 | pmid = 12167712 | pmc = 134012 | doi = 10.1128/MCB.22.17.6183-6198.2002 | language = en | issn = 1098-5549 }}{{Cite journal | vauthors = Cohen N | title = PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA | journal = The EMBO Journal | volume = 20 | issue = 16 | pages = 4547–4559 | date = 2001-08-15 | pmid = 11500381 | pmc = 125576 | doi = 10.1093/emboj/20.16.4547 | url = http://emboj.embopress.org/cgi/doi/10.1093/emboj/20.16.4547 }}{{Cite journal | vauthors = Topisirovic I | title = The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth | journal = The EMBO Journal | volume = 22 | issue = 3 | pages = 689–703 | date = 2003-02-03 | pmid = 12554669 | pmc = 140753 | doi = 10.1093/emboj/cdg069 | url = http://emboj.embopress.org/cgi/doi/10.1093/emboj/cdg069 }}{{Cite journal | vauthors = Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL | title = eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR | journal = The Journal of Cell Biology | volume = 169 | issue = 2 | pages = 245–256 | date = 2005-04-25 | pmid = 15837800 | pmc = 2171863 | doi = 10.1083/jcb.200501019 | url = https://rupress.org/jcb/article/169/2/245/51714/eIF4E-promotes-nuclear-export-of-cyclin-D1-mRNAs | language = en | issn = 1540-8140 }}

Function

This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E plays a central role in the translation of mRNAs by directing ribosomes to the cap structure at the 5'-end of mRNAs, and is considered by some to be the rate-limiting component of the eukaryotic translation apparatus. Many cellular mRNAs require eIF4E for translation into protein.

Some viruses cleave eIF4G in such a way that the eIF4E binding site is removed, allowing viral RNAs to be translated independently of eIF4E. Similarly, some cellular mRNAs, such as those encoding heat shock proteins, utilize internal ribosome entry site (IRES) elements or other mechanisms, including translation initiation via eIF3d.{{Cite journal | vauthors = de la Parra C, Ernlund A, Alard A, Ruggles K, Ueberheide B, Schneider RJ | title = A widespread alternate form of cap-dependent mRNA translation initiation | journal = Nature Communications | volume = 9 | issue = 1 | pages = 3068 | date = 2018-08-03 | pmid = 30076308 | pmc = 6076257 | doi = 10.1038/s41467-018-05539-0 | language = en | issn = 2041-1723 | bibcode = 2018NatCo...9.3068D }}{{Cite journal | vauthors = Lee AS, Kranzusch PJ, Doudna JA, Cate JH | title = eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation | journal = Nature | volume = 536 | issue = 7614 | pages = 96–99 | date = 2016-08-04 | pmid = 27462815 | pmc = 5003174 | doi = 10.1038/nature18954 | language = en | issn = 0028-0836 | bibcode = 2016Natur.536...96L }}

In addition, alternative cap-binding proteins such as eIF3D, eIF3I, PARN, and the nuclear cap-binding complex (CBC) can support cap-dependent translation in specific contexts, particularly when eIF4E activity is limited or bypassed.{{Cite journal | vauthors = Bukhari SI, Truesdell SS, Lee S, Kollu S, Classon A, Boukhali M, Jain E, Mortensen RD, Yanagiya A, Sadreyev RI, Haas W, Vasudevan S | title = A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence | journal = Molecular Cell | volume = 61 | issue = 5 | pages = 760–773 | date = March 2016 | pmid = 26942679 | pmc = 4811377 | doi = 10.1016/j.molcel.2016.02.013 | language = en }}{{Cite journal | vauthors = Kumar P, Hellen CU, Pestova TV | title = Toward the mechanism of eIF4F-mediated ribosomal attachment to mammalian capped mRNAs | journal = Genes & Development | volume = 30 | issue = 13 | pages = 1573–1588 | date = 2016-07-01 | pmid = 27401559 | pmc = 4949329 | doi = 10.1101/gad.282418.116 | language = en | issn = 0890-9369 }}{{Cite journal | vauthors = Borden KL, Volpon L | title = The diversity, plasticity, and adaptability of cap-dependent translation initiation and the associated machinery | journal = RNA Biology | volume = 17 | issue = 9 | pages = 1239–1251 | date = 2020-09-01 | pmid = 32496897 | pmc = 7549709 | doi = 10.1080/15476286.2020.1766179 | language = en | issn = 1547-6286 }}

Nuclear eIF4E plays defined roles in mRNA export, particularly for transcripts that contain a 50-nucleotide eIF4E sensitivity element (4ESE) in the 3′ UTR. This process depends on eIF4E’s cap-binding ability and the CRM1/XPO1 nuclear export pathway, and is facilitated by the adaptor protein LRPPRC which simultaneously binds to eIF4E and the 4ESE-containing RNA.{{Cite journal | vauthors = Topisirovic I, Siddiqui N, Lapointe VL, Trost M, Thibault P, Bangeranye C, Piñol-Roma S, Borden KL | title = Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP | journal = The EMBO Journal | volume = 28 | issue = 8 | pages = 1087–1098 | date = 2009-04-22 | pmid = 19262567 | pmc = 2683702 | doi = 10.1038/emboj.2009.53 | issn = 0261-4189 }}{{Cite journal | vauthors = Volpon L, Culjkovic-Kraljacic B, Sohn HS, Blanchet-Cohen A, Osborne MJ, Borden KL | title = A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery | journal = RNA | location = New York, N.Y. | volume = 23 | issue = 6 | pages = 927–937 | date = June 2017 | pmid = 28325843 | pmc = 5435865 | doi = 10.1261/rna.060137.116 | language = en | issn = 1355-8382 }}

Moreover, eIF4E influences RNA processing events such as alternative splicing, 3′-end cleavage, and m⁷G capping, and increased nuclear eIF4E activity is associated with oncogenic phenotypes in cancers such as acute myeloid leukemia (AML).{{Cite journal | vauthors = Culjkovic-Kraljacic B, Skrabanek L, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L, Borden KL | title = The eukaryotic translation initiation factor eIF4E elevates steady-state m 7 G capping of coding and noncoding transcripts | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 43 | pages = 26773–26783 | date = 2020-10-27 | pmid = 33055213 | pmc = 7604501 | doi = 10.1073/pnas.2002360117 | language = en | issn = 0027-8424 | bibcode = 2020PNAS..11726773C | doi-access = free }}{{Cite journal | vauthors = Ghram M, Morris G, Culjkovic-Kraljacic B, Mars JC, Gendron P, Skrabanek L, Revuelta MV, Cerchietti L, Guzman ML, Borden KL | title = The eukaryotic translation initiation factor eIF4E reprograms alternative splicing | journal = The EMBO Journal | volume = 42 | issue = 7 | pages = e110496 | date = 2023-04-03 | pmid = 36843541 | pmc = 10068332 | doi = 10.15252/embj.2021110496 | language = en | issn = 0261-4189 }}{{Cite journal | vauthors = Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber B, Roy DC, Miller WH, Borden KL | title = Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin | journal = Blood | volume = 114 | issue = 2 | pages = 257–260 | date = 2009-07-09 | pmid = 19433856 | doi = 10.1182/blood-2009-02-205153 | url = https://ashpublications.org/blood/article/114/2/257/26204/Molecular-targeting-of-the-oncogene-eIF4E-in-acute | language = en | s2cid = 28957125 | issn = 0006-4971 | doi-access = free }} Through its coordinated activity in RNA export and translation, eIF4E can effectively reprogram the transcriptome and proteome of the cell, earning the designation of a “cap-chaperone” protein.

Regulation

Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E can be controlled at multiple levels.{{Cite journal | vauthors = Duncan R, Milburn SC, Hershey JW | title = Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F | journal = The Journal of Biological Chemistry | volume = 262 | issue = 1 | pages = 380–388 | date = 1987-01-05 | pmid = 3793730 | doi = 10.1016/S0021-9258(19)75938-9 | issn = 0021-9258 | doi-access = free }}{{Cite journal | vauthors = Mars JC, Ghram M, Culjkovic-Kraljacic B, Borden KL | title = The Cap-Binding Complex CBC and the Eukaryotic Translation Factor eIF4E: Co-Conspirators in Cap-Dependent RNA Maturation and Translation | journal = Cancers | volume = 13 | issue = 24 | pages = 6185 | date = 2021-12-08 | pmid = 34944805 | pmc = 8699206 | doi = 10.3390/cancers13246185 | language = en | issn = 2072-6694 | doi-access = free }} Regulation of eIF4E may be achieved at the levels of transcription, RNA stability phosphorylation, subcellular localization and partner proteins.{{Cite journal | vauthors = Richter JD, Sonenberg N | title = Regulation of cap-dependent translation by eIF4E inhibitory proteins | journal = Nature | volume = 433 | issue = 7025 | pages = 477–480 | date = 2005-02-03 | pmid = 15690031 | doi = 10.1038/nature03205 | issn = 1476-4687 | bibcode = 2005Natur.433..477R | s2cid = 4347657 | url = https://escholarship.mcgill.ca/concern/articles/k930c3532 }}

= Gene expression and RNA stability =

The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle.{{Cite journal | vauthors = Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV | title = Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 13 | pages = 6175–6178 | date = 1993-07-01 | pmid = 8327497 | pmc = 46890 | doi = 10.1073/pnas.90.13.6175 | issn = 0027-8424 | bibcode = 1993PNAS...90.6175R | doi-access = free }} The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene.{{Cite journal | vauthors = Jones RM, Branda J, Johnston KA, Polymenis M, Gadd M, Rustgi A, Callanan L, Schmidt EV | title = An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc | journal = Molecular and Cellular Biology | volume = 16 | issue = 9 | pages = 4754–4764 | date = September 1996 | pmid = 8756633 | pmc = 231476 | doi = 10.1128/mcb.16.9.4754 | issn = 0270-7306 }} This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.

Recent studies shown that eIF4E levels can be regulated at transcriptional level by NFkB and C/EBP.{{Cite journal | vauthors = Khanna-Gupta A, Abayasekara N, Levine M, Sun H, Virgilio M, Nia N, Halene S, Sportoletti P, Jeong JY, Pandolfi PP, Berliner N | title = Up-regulation of Translation Eukaryotic Initiation Factor 4E in Nucleophosmin 1 Haploinsufficient Cells Results in Changes in CCAAT Enhancer-binding Protein α Activity | journal = The Journal of Biological Chemistry | volume = 287 | issue = 39 | pages = 32728–32737 | date = September 2012 | pmid = 22851180 | pmc = 3463350 | doi = 10.1074/jbc.M112.373274 | language = en | doi-access = free }}{{Cite journal | vauthors = Hariri F, Arguello M, Volpon L, Culjkovic-Kraljacic B, Nielsen TH, Hiscott J, Mann KK, Borden KL | title = The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia | journal = Leukemia | volume = 27 | issue = 10 | pages = 2047–2055 | date = October 2013 | pmid = 23467026 | pmc = 4429918 | doi = 10.1038/leu.2013.73 | language = en | issn = 0887-6924 }} Transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein. eIF4E mRNA stability are also regulated by HuR and TIAR proteins.{{Cite journal | vauthors = Mazan-Mamczarz K, Lal A, Martindale JL, Kawai T, Gorospe M | title = Translational Repression by RNA-Binding Protein TIAR | journal = Molecular and Cellular Biology | volume = 26 | issue = 7 | pages = 2716–2727 | date = 2006-04-01 | pmid = 16537914 | pmc = 1430315 | doi = 10.1128/MCB.26.7.2716-2727.2006 | language = en | issn = 1098-5549 }}{{Cite journal | vauthors = Topisirovic I, Siddiqui N, Orolicki S, Skrabanek LA, Tremblay M, Hoang T, Borden KL | title = Stability of Eukaryotic Translation Initiation Factor 4E mRNA Is Regulated by HuR, and This Activity Is Dysregulated in Cancer | journal = Molecular and Cellular Biology | volume = 29 | issue = 5 | pages = 1152–1162 | date = 2009-03-01 | pmid = 19114552 | pmc = 2643828 | doi = 10.1128/MCB.01532-08 | language = en | issn = 1098-5549 }} eIF4E gene amplification has been observed in subset of head and neck and breast cancer specimens.{{Cite journal | vauthors = Sorrells DL, Black DR, Meschonat C, Rhoads R, De Benedetti A, Gao M, Williams BJ, Li BD | title = Detection of eIF4E gene amplification in breast cancer by competitive PCR | journal = Annals of Surgical Oncology | volume = 5 | issue = 3 | pages = 232–237 | date = April 1998 | pmid = 9607624 | doi = 10.1007/BF02303778 | url = http://link.springer.com/10.1007/BF02303778 | language = en | s2cid = 776478 | issn = 1068-9265 | url-access = subscription }}

= Phosphorylation =

Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E.{{Cite journal | vauthors = Morley SJ, Traugh JA | title = Differential stimulation of phosphorylation of initiation factors eIF-4F, eIF-4B, eIF-3, and ribosomal protein S6 by insulin and phorbol esters | journal = The Journal of Biological Chemistry | volume = 265 | issue = 18 | pages = 10611–10616 | date = 1990-06-25 | pmid = 2191953 | doi = 10.1016/S0021-9258(18)86990-3 | issn = 0021-9258 | doi-access = free }} Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G₀ and M phase and wherein high phosphorylation is seen during G₁ and S phase.{{Cite journal | vauthors = Bonneau AM, Sonenberg N | title = Involvement of the 24-kDa cap-binding protein in regulation of protein synthesis in mitosis | journal = The Journal of Biological Chemistry | volume = 262 | issue = 23 | pages = 11134–11139 | date = 1987-08-15 | pmid = 3038908 | doi = 10.1016/S0021-9258(18)60935-4 | issn = 0021-9258 | doi-access = free }} This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.

eIF4E phosphorylation is also related to its ability to suppress RNA export and its oncogenic potential as first shown in cell lines.{{Cite journal | vauthors = Topisirovic I, Ruiz-Gutierrez M, Borden KL | title = Phosphorylation of the Eukaryotic Translation Initiation Factor eIF4E Contributes to Its Transformation and mRNA Transport Activities | journal = Cancer Research | volume = 64 | issue = 23 | pages = 8639–8642 | date = 2004-12-01 | pmid = 15574771 | doi = 10.1158/0008-5472.CAN-04-2677 | language = en | s2cid = 21104713 | issn = 0008-5472 | doi-access = free }}

= Partner proteins =

Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation. Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation.{{Cite journal | vauthors = Peter D, Igreja C, Weber R, Wohlbold L, Weiler C, Ebertsch L, Weichenrieder O, Izaurralde E | title = Molecular architecture of 4E-BP translational inhibitors bound to eIF4E | journal = Molecular Cell | volume = 57 | issue = 6 | pages = 1074–1087 | date = 2015-03-19 | pmid = 25702871 | doi = 10.1016/j.molcel.2015.01.017 | issn = 1097-4164 | doi-access = free }} Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E.{{Cite journal | vauthors = Whalen SG, Gingras AC, Amankwa L, Mader S, Branton PE, Aebersold R, Sonenberg N | title = Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins | journal = The Journal of Biological Chemistry | volume = 271 | issue = 20 | pages = 11831–11837 | date = 1996-05-17 | pmid = 8662663 | doi = 10.1074/jbc.271.20.11831 | issn = 0021-9258 | doi-access = free }} Of note, 4E-BP1 is found in both the nucleus and the cytoplasm, indicating that it likely modulates nuclear eIF4Es functions of eIF4E as well.{{Cite journal | vauthors = Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras AC, Crosby K, Smith B, Polakiewicz RD, Pelletier J, Ferraiuolo MA, Sonenberg N | title = Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs | journal = RNA | location = New York, N.Y. | volume = 14 | issue = 7 | pages = 1318–1327 | date = July 2008 | pmid = 18515545 | pmc = 2441981 | doi = 10.1261/rna.950608 | language = en | issn = 1355-8382 }} A recent study showed that 4E-BP3 regulated eIF4E dependent mRNA nucleo-cytoplasmic export.{{Cite journal | vauthors = Chen CC, Lee JC, Chang MC | title = 4E-BP3 regulates eIF4E-mediated nuclear mRNA export and interacts with replication protein A2 | journal = FEBS Letters | volume = 586 | issue = 16 | pages = 2260–2266 | date = 2012-07-30 | pmid = 22684010 | doi = 10.1016/j.febslet.2012.05.059 | language = en | s2cid = 40980342 | doi-access = free | bibcode = 2012FEBSL.586.2260C }} There are also many cytoplasmic regulators of eIF4E that bind to the same site as 4E-BP1.

Many other partner proteins has been found that can both stimulate or repress eIF4E activity, such as homeodomain containing proteins, including HoxA9, Hex/PRH, Hox 11, Bicoid, Emx-2 and Engrailed 2.{{Cite journal | vauthors = Niessing D, Blanke S, Jäckle H | title = Bicoid associates with the 5′-cap-bound complex of caudal mRNA and represses translation | journal = Genes & Development | volume = 16 | issue = 19 | pages = 2576–2582 | date = 2002-10-01 | pmid = 12368268 | pmc = 187448 | doi = 10.1101/gad.240002 | language = en | issn = 0890-9369 }}{{Cite journal | vauthors = Nédélec S, Foucher I, Brunet I, Bouillot C, Prochiantz A, Trembleau A | title = Emx2 homeodomain transcription factor interacts with eukaryotic translation initiation factor 4E (eIF4E) in the axons of olfactory sensory neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10815–10820 | date = 2004-07-20 | pmid = 15247416 | pmc = 490017 | doi = 10.1073/pnas.0403824101 | language = en | issn = 0027-8424 | bibcode = 2004PNAS..10110815N | doi-access = free }}{{Cite journal | vauthors = Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, Holt C | title = The transcription factor Engrailed-2 guides retinal axons | journal = Nature | volume = 438 | issue = 7064 | pages = 94–98 | date = November 2005 | pmid = 16267555 | pmc = 3785142 | doi = 10.1038/nature04110 | language = en | issn = 0028-0836 | bibcode = 2005Natur.438...94B }}{{Cite journal | vauthors = Topisirovic I, Borden KL | title = Homeodomain proteins and eukaryotic translation initiation factor 4E (eIF4E): an unexpected relationship | journal = Histology and Histopathology | volume = 20 | issue = 4 | pages = 1275–1284 | date = October 2005 | pmid = 16136508 | doi = 10.14670/hh-20.1275 | issn = 0213-3911 }} While HoxA9 promotes mRNA export and translation activities of eIF4E, Hex/PRH inhibits nuclear functions of eIF4E.{{Cite journal | vauthors = Kuroda N, Guo L, Miyazaki E, Hamauzu T, Toi M, Hiroi M, Enzan H | title = The appearance of myofibroblasts and the disappearance of CD34-positive stromal cells in the area adjacent to xanthogranulomatous foci of chronic cholecystitis | journal = Histology and Histopathology | volume = 20 | issue = 1 | pages = 127–133 | date = 2005-01-01 | pmid = 15578431 | doi = 10.14670/hh-20.127 | issn = 0213-3911 }}{{Cite journal | vauthors = Topisirovic I, Kentsis A, Perez JM, Guzman ML, Jordan CT, Borden KL | title = Eukaryotic Translation Initiation Factor 4E Activity Is Modulated by HOXA9 at Multiple Levels | journal = Molecular and Cellular Biology | volume = 25 | issue = 3 | pages = 1100–1112 | date = 2005-02-01 | pmid = 15657436 | pmc = 544005 | doi = 10.1128/MCB.25.3.1100-1112.2005 | language = en | issn = 1098-5549 }} The RNA helicase DDX3 directly binds with eIF4E, modulates translation, and has potential functions in P-bodies and mRNA export.{{Cite journal | vauthors = Shih JW, Tsai TY, Chao CH, Wu Lee YH | title = Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein | journal = Oncogene | volume = 27 | issue = 5 | pages = 700–714 | date = 2008-01-24 | pmid = 17667941 | doi = 10.1038/sj.onc.1210687 | language = en | s2cid = 19781838 | issn = 0950-9232 | doi-access = free }}

RING domains also bind eIF4E. The promyelocytic leukemia protein PML is a potent suppressor of both the nuclear RNA export and oncogenic activities of eIF4E whereby the RING domain of PML directly binds eIF4E on its dorsal surface suppressing eIF4E's oncogenic activity; and moreover a subset of PML and eIF4E nuclear bodies co-localize.{{Cite journal | vauthors = Kentsis A, Gordon RE, Borden KL | title = Control of biochemical reactions through supramolecular RING domain self-assembly | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 24 | pages = 15404–15409 | date = 2002-11-26 | pmid = 12438698 | pmc = 137729 | doi = 10.1073/pnas.202608799 | language = en | issn = 0027-8424 | bibcode = 2002PNAS...9915404K | doi-access = free }}{{Cite journal | vauthors = Kentsis A, Dwyer EC, Perez JM, Sharma M, Chen A, Pan ZQ, Borden KL | title = The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E 1 1Edited by D. Draper | journal = Journal of Molecular Biology | volume = 312 | issue = 4 | pages = 609–623 | date = September 2001 | pmid = 11575918 | doi = 10.1006/jmbi.2001.5003 | url = https://linkinghub.elsevier.com/retrieve/pii/S002228360195003X | language = en | url-access = subscription }}{{Cite journal | vauthors = Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL | title = eIF4E is a central node of an RNA regulon that governs cellular proliferation | journal = The Journal of Cell Biology | volume = 175 | issue = 3 | pages = 415–426 | date = 2006-11-06 | pmid = 17074885 | pmc = 2064519 | doi = 10.1083/jcb.200607020 | url = https://rupress.org/jcb/article/175/3/415/34316/eIF4E-is-a-central-node-of-an-RNA-regulon-that | language = en | issn = 1540-8140 }} RNA-eIF4E complexes are never observed in PML bodies consistent with the observation that PML suppresses the m7G cap binding function of eIF4E. Structural studies show that a related arenavirus RING finger protein, Lassa Fever Z protein, can similarly bind eIF4E on the dorsal surface.{{Cite journal | vauthors = Kentsis A, Gordon RE, Borden KL | title = Self-assembly properties of a model RING domain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 2 | pages = 667–672 | date = 2002-01-22 | pmid = 11792829 | pmc = 117363 | doi = 10.1073/pnas.012317299 | language = en | issn = 0027-8424 | doi-access = free }}{{Cite journal | vauthors = Volpon L, Osborne MJ, Capul AA, de la Torre JC, Borden KL | title = Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 12 | pages = 5441–5446 | date = 2010-03-23 | pmid = 20212144 | pmc = 2851782 | doi = 10.1073/pnas.0909877107 | language = en | issn = 0027-8424 | bibcode = 2010PNAS..107.5441V | doi-access = free }}

eIF4E nuclear entry is mediated by its direct interactions with Importin 8 where Importin 8 associates with the m7G cap-binding site of eIF4E.{{Cite journal | vauthors = Volpon L, Culjkovic-Kraljacic B, Osborne MJ, Ramteke A, Sun Q, Niesman A, Chook YM, Borden KL | title = Importin 8 mediates m 7 G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 19 | pages = 5263–5268 | date = 2016-05-10 | pmid = 27114554 | pmc = 4868427 | doi = 10.1073/pnas.1524291113 | language = en | issn = 0027-8424 | bibcode = 2016PNAS..113.5263V | doi-access = free }} Indeed, reduction in Importin 8 levels reduce the oncogenic potential of eIF4E overexpressing cells and its RNA export function. Importin 8 binds to the cap-binding site of eIF4E and is competed by excess m⁷G cap analogues as observed by NMR. eIF4E also stimulates the RNA export of Importin 8 RNA thereby producing more Importin 8 protein. There may be additional importins that play this role depending on cell type. Although an initial study suggested that the eIF4E transporter protein 4E-T (eIF4ENIF1) facilitated nuclear entry, later studies showed that this factor rather alters the localization of eIF4E to cytoplasmic processing bodies (P-bodies) and repress translation.{{Cite journal | vauthors = Ferraiuolo MA, Basak S, Dostie J, Murray EL, Schoenberg DR, Sonenberg N | title = A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay | journal = The Journal of Cell Biology | volume = 170 | issue = 6 | pages = 913–924 | date = 2005-09-12 | pmid = 16157702 | pmc = 2171455 | doi = 10.1083/jcb.200504039 | url = https://rupress.org/jcb/article/170/6/913/51932/A-role-for-the-eIF4Ebinding-protein-4ET-in-Pbody | language = en | issn = 1540-8140 }}

Potyvirus viral protein genome linked (VPg) were found to directly bind eIF4E in its cap-binding site. VPg is covalently linked to its genomic RNA and this interaction allows VPg to act as a "cap."{{Cite journal | vauthors = German-Retana S, Walter J, Le Gall O | title = Lettuce mosaic virus: from pathogen diversity to host interactors | journal = Molecular Plant Pathology | volume = 9 | issue = 2 | pages = 127–136 | date = March 2008 | pmid = 18705846 | pmc = 6640324 | doi = 10.1111/j.1364-3703.2007.00451.x | bibcode = 2008MolPP...9..127G | language = en | issn = 1464-6722 }}{{Cite journal | vauthors = Coutinho de Oliveira L, Volpon L, Osborne MJ, Borden KL | title = Chemical shift assignment of the viral protein genome-linked (VPg) from potato virus Y | journal = Biomolecular NMR Assignments | volume = 13 | issue = 1 | pages = 9–13 | date = April 2019 | pmid = 30242622 | pmc = 6428624 | doi = 10.1007/s12104-018-9842-3 | language = en | issn = 1874-2718 }}{{Cite journal | vauthors = Coutinho de Oliveira L, Volpon L, Rahardjo AK, Osborne MJ, Culjkovic-Kraljacic B, Trahan C, Oeffinger M, Kwok BH, Borden KL | title = Structural studies of the eIF4E–VPg complex reveal a direct competition for capped RNA: Implications for translation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 48 | pages = 24056–24065 | date = 2019-11-26 | pmid = 31712417 | pmc = 6883836 | doi = 10.1073/pnas.1904752116 | language = en | issn = 0027-8424 | bibcode = 2019PNAS..11624056C | doi-access = free }} The potyvirus VPg has no sequence or structural homology to other VPg's such as those from poliovirus. In vitro, VPg-RNA conjugates were translated with similar efficiency to m⁷G-capped RNAs indicating that VPg binds eIF4E and engages the translation machinery; while free VPg (in the absence of conjugated RNA) successfully competes for all the cap-dependent activities of eIF4E in the cell inhibiting translation and RNA export.

= Cellular localization =

Several factors that regulate eIF4E functions also modulate the subcellular localization of eIF4E. For instance, overexpression of PRH/Hex leads to cytoplasmic retention of eIF4E, and thus loss of its mRNA export activity and suppression of transformation. PML overexpression leads to sequestration of eIF4E to nuclear bodies with PML and decrease of eIF4E nuclear bodies containing RNA, which correlates to repressed eIF4E dependent mRNA export and can be modulated by stress. Overexpression of LRPPRC reduces eIF4E’s co-localization with PML in the nucleus and leads to increased mRNA export activity of eIF4E. As discussed above, Importin 8 brings eIF4E into the nucleus and its overexpression stimulates the RNA export and oncogenic transformation activities of eIF4E in cell lines. Transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein.

Role in cancer

Lazaris-Karatzas et al.{{Cite journal |vauthors=Lazaris-Karatzas A, Montine KS, Sonenberg N |date=1990-06-07 |title=Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap |journal=Nature |volume=345 |issue=6275 |pages=544–547 |bibcode=1990Natur.345..544L |doi=10.1038/345544a0 |issn=0028-0836 |pmid=2348862 |s2cid=4366949}} found that that over-expressing eIF4E causes tumorigenic transformation of fibroblasts. Since this initial observation, numerous groups have recapitulated these results in different cell lines.{{Cite journal | vauthors = Pelletier J, Graff J, Ruggero D, Sonenberg N | title = TARGETING THE eIF4F TRANSLATION INITIATION COMPLEX: A CRITICAL NEXUS FOR CANCER DEVELOPMENT | journal = Cancer Research | volume = 75 | issue = 2 | pages = 250–263 | date = 2015-01-15 | pmid = 25593033 | pmc = 4299928 | doi = 10.1158/0008-5472.CAN-14-2789 | issn = 0008-5472 }} As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated.{{Cite journal | vauthors = Ramaswamy S, Ross KN, Lander ES, Golub TR | title = A molecular signature of metastasis in primary solid tumors | journal = Nature Genetics | volume = 33 | issue = 1 | pages = 49–54 | date = January 2003 | pmid = 12469122 | doi = 10.1038/ng1060 | language = En | s2cid = 12059602 | issn = 1546-1718 }}

eIF4E levels are increased in many cancers including acute myeloid leukemia (AML), multiple myeloma, infant ALL, diffuse large B-cell lymphoma, breast cancer, prostate cancer, head and neck cancer and its elevation generally correlates with poor prognosis.{{Cite journal | vauthors = Culjkovic B, Borden KL | title = Understanding and Targeting the Eukaryotic Translation Initiation Factor eIF4E in Head and Neck Cancer | journal = Journal of Oncology | volume = 2009 | pages = 981679 | date = 2009 | pmid = 20049173 | pmc = 2798714 | doi = 10.1155/2009/981679 | language = en | issn = 1687-8450 | doi-access = free }}{{Cite journal | vauthors = Pettersson F, Yau C, Dobocan MC, Culjkovic-Kraljacic B, Retrouvay H, Puckett R, Flores LM, Krop IE, Rousseau C, Cocolakis E, Borden KL, Benz CC, Miller WH | title = Ribavirin Treatment Effects on Breast Cancers Overexpressing eIF4E, a Biomarker with Prognostic Specificity for Luminal B-Type Breast Cancer | journal = Clinical Cancer Research | volume = 17 | issue = 9 | pages = 2874–2884 | date = 2011-05-01 | pmid = 21415224 | pmc = 3086959 | doi = 10.1158/1078-0432.CCR-10-2334 | language = en | issn = 1078-0432 }}{{Cite journal | vauthors = Assouline S, Culjkovic-Kraljacic B, Bergeron J, Caplan S, Cocolakis E, Lambert C, Lau CJ, Zahreddine HA, Miller WH, Borden KL | title = A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E | journal = Haematologica | volume = 100 | issue = 1 | pages = e7–e9 | date = 2015-01-01 | pmid = 25425688 | pmc = 4281321 | doi = 10.3324/haematol.2014.111245 | language = en | issn = 0390-6078 }}{{Cite journal | vauthors = Attar-Schneider O, Pasmanik-Chor M, Tartakover-Matalon S, Drucker L, Lishner M | title = eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling | journal = Oncotarget | volume = 6 | issue = 6 | pages = 4315–4329 | date = 2015-02-28 | pmid = 25717031 | pmc = 4414192 | doi = 10.18632/oncotarget.3008 | language = en | issn = 1949-2553 }}{{Cite journal | vauthors = Zismanov V, Attar-Schneider O, Lishner M, Aizenfeld RH, Matalon ST, Drucker L | title = Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E | journal = International Journal of Oncology | volume = 46 | issue = 2 | pages = 860–870 | date = February 2015 | pmid = 25422161 | doi = 10.3892/ijo.2014.2774 | language = en | issn = 1019-6439 | doi-access = free }}{{Cite journal | vauthors = Dunn LA, Fury MG, Sherman EJ, Ho AA, Katabi N, Haque SS, Pfister DG | title = Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer | journal = Head & Neck | volume = 40 | issue = 2 | pages = 233–241 | date = February 2018 | pmid = 28963790 | pmc = 6760238 | doi = 10.1002/hed.24938 | language = en }}{{Cite journal | vauthors = Urtishak KA, Wang LS, Culjkovic-Kraljacic B, Davenport JW, Porazzi P, Vincent TL, Teachey DT, Tasian SK, Moore JS, Seif AE, Jin S, Barrett JS, Robinson BW, Chen IM, Harvey RC | title = Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia | journal = Oncogene | volume = 38 | issue = 13 | pages = 2241–2262 | date = 2019-03-28 | pmid = 30478448 | pmc = 6440839 | doi = 10.1038/s41388-018-0567-7 | language = en | issn = 0950-9232 }} In many of these cancers such as AML, eIF4E is enriched in nuclei and several of eIF4E’s activities are found to be elevated in primary patient specimens, including capping, splicing, RNA export, and translation.

In the first clinical trials targeting eIF4E, old antiviral drug ribavirin was used as a m7G cap competitor which had substantial activity in cancer cell lines and animal models associated with dysregulated eIF4E.{{Cite journal | vauthors = Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL | title = Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 52 | pages = 18105–18110 | date = 2004-12-28 | pmid = 15601771 | pmc = 539790 | doi = 10.1073/pnas.0406927102 | language = en | issn = 0027-8424 | bibcode = 2004PNAS..10118105K | doi-access = free }}{{Cite journal | vauthors = Kentsis A, Volpon L, Topisirovic I, Soll CE, Culjkovic B, Shao L, Borden KL | title = Further evidence that ribavirin interacts with eIF4E | journal = RNA | location = New York, N.Y. | volume = 11 | issue = 12 | pages = 1762–1766 | 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anti-glioblastoma therapeutic | journal = Oncogene | volume = 36 | issue = 21 | pages = 3037–3047 | date = 2017-05-25 | pmid = 27941882 | doi = 10.1038/onc.2016.457 | url = https://www.nature.com/articles/onc2016457 | language = en | s2cid = 21655102 | issn = 0950-9232 | url-access = subscription }}{{Cite journal | vauthors = Wang G, Li Z, Li Z, Huang Y, Mao X, Xu C, Cui S | title = Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy | journal = Biomedicine & Pharmacotherapy | volume = 96 | pages = 750–756 | date = December 2017 | pmid = 29049978 | doi = 10.1016/j.biopha.2017.10.034 | url = https://linkinghub.elsevier.com/retrieve/pii/S0753332217346772 | language = en | url-access = subscription }}{{Cite journal | vauthors = Xi C, Wang L, Yu J, Ye H, Cao L, Gong Z | title = Inhibition of eukaryotic translation initiation factor 4E is effective against chemo-resistance in colon and cervical cancer | journal = Biochemical and Biophysical Research Communications | volume = 503 | issue = 4 | pages = 2286–2292 | date = September 2018 | pmid = 29959920 | doi = 10.1016/j.bbrc.2018.06.150 | url = https://linkinghub.elsevier.com/retrieve/pii/S0006291X18314694 | language = en | s2cid = 49634908 | url-access = subscription }}{{Cite journal | vauthors = Jin J, Xiang W, Wu S, Wang M, Xiao M, Deng A | title = Targeting eIF4E signaling with ribavirin as a sensitizing strategy for ovarian cancer | journal = Biochemical and Biophysical Research Communications | volume = 510 | issue = 4 | pages = 580–586 | date = March 2019 | pmid = 30739792 | doi = 10.1016/j.bbrc.2019.01.117 | url = https://linkinghub.elsevier.com/retrieve/pii/S0006291X19301469 | language = en | s2cid = 73419809 | url-access = subscription }} In the first trial to ever target eIF4E, ribavirin monotherapy was demonstrated to inhibit eIF4E activity leading to objective clinical responses including complete remissions in AML patients. Interestingly, relocalization of eIF4E from the nucleus to the cytoplasm correlated with clinical remissions indicative of the relevance of its nuclear activities to disease progression. Subsequent ribavirin trials in AML in combination with antileukemic drugs again showed objective clinical responses including remissions and molecular targeting of eIF4E.{{Cite journal | vauthors = Assouline S, Gasiorek J, Bergeron J, Lambert C, Culjkovic-Kraljacic B, Cocolakis E, Zakaria C, Szlachtycz D, Yee K, Borden KL | title = Molecular targeting of the UDP-glucuronosyltransferase enzymes in high-eukaryotic translation initiation factor 4E refractory/relapsed acute myeloid leukemia patients: a randomized phase II trial of vismodegib, ribavirin with or without decitabine | journal = Haematologica | volume = 108 | issue = 11 | pages = 2946–2958 | date = 2023-03-23 | pmid = 36951168 | pmc = 10620574 | doi = 10.3324/haematol.2023.282791 | s2cid = 257733013 | issn = 1592-8721 | doi-access = free }} Clinical responses correlated with reduced nuclear eIF4E and clinical relapse with re-emergence of eIF4E nuclear eIF4E and its RNA export activity in these AML studies. Other studies used ribavirin in combination showed similar promising results in head and neck cancer. Ribavirin impairs all of the activities of eIF4E examined to date (splicing, capping, RNA export and translation). Thus, eIF4E has been successfully therapeutically targetable in humans; however drug resistance to ribavirin is an emergent problem to long term disease control.

eIF4E has also been targeted by antisense oligonucleotides which were very potent in mouse models of prostate cancer,{{Cite journal | vauthors = Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, Schwier P, Capen A, Goode RL, Dowless MS, Chen Y, Zhang H, Sissons S, Cox K, McNulty AM | title = Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity | journal = The Journal of Clinical Investigation | volume = 117 | issue = 9 | pages = 2638–2648 | date = 2007-09-04 | pmid = 17786246 | pmc = 1957541 | doi = 10.1172/JCI32044 | language = en | issn = 0021-9738 }} but in monotherapy trials in humans did not provide clinical benefit likely due to the inefficiency of reducing eIF4E levels in humans compared to mice.{{Cite journal | vauthors = Hong DS, Kurzrock R, Oh Y, Wheler J, Naing A, Brail L, Callies S, André V, Kadam SK, Nasir A, Holzer TR, Meric-Bernstam F, Fishman M, Simon G | title = A Phase 1 Dose Escalation, Pharmacokinetic, and Pharmacodynamic Evaluation of eIF-4E Antisense Oligonucleotide LY2275796 in Patients with Advanced Cancer | journal = Clinical Cancer Research | volume = 17 | issue = 20 | pages = 6582–6591 | date = 2011-10-15 | pmid = 21831956 | pmc = 5036398 | doi = 10.1158/1078-0432.CCR-11-0430 | language = en | issn = 1078-0432 }} There is also an allosteric inhibitor of eIF4E which binds between the cap-binding site and the dorsal surface that is used experimentally.{{Cite journal | vauthors = Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA | title = Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 31 | pages = E3187–E3195 | date = 2014-08-05 | pmid = 25049413 | pmc = 4128100 | doi = 10.1073/pnas.1410250111 | language = en | issn = 0027-8424 | bibcode = 2014PNAS..111E3187P | doi-access = free }}

FMRP repression of translation

Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1.{{cite journal | vauthors = Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C | title = The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP | journal = Cell | volume = 134 | issue = 6 | pages = 1042–1054 | date = September 2008 | pmid = 18805096 | doi = 10.1016/j.cell.2008.07.031 | s2cid = 14123165 | doi-access = free }} RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.{{cite journal | vauthors = Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C | title = The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses | journal = Cell | volume = 112 | issue = 3 | pages = 317–327 | date = February 2003 | pmid = 12581522 | doi = 10.1016/S0092-8674(03)00079-5 | s2cid = 14892764 | doi-access = free }}

In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.

Interactions

EIF4E has been shown to interact with:

EIF4A1,{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}{{cite journal | vauthors = Connolly E, Braunstein S, Formenti S, Schneider RJ | title = Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells | journal = Molecular and Cellular Biology | volume = 26 | issue = 10 | pages = 3955–3965 | date = May 2006 | pmid = 16648488 | pmc = 1489005 | doi = 10.1128/MCB.26.10.3955-3965.2006 }}
EIF4EBP1,{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}{{cite journal | vauthors = Mader S, Lee H, Pause A, Sonenberg N | title = 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 | journal = Molecular and Cellular Biology | volume = 15 | issue = 9 | pages = 4990–4997 | date = September 1995 | pmid = 7651417 | pmc = 230746 | doi = 10.1128/MCB.15.9.4990 }}{{cite journal | vauthors = Rao RD, Mladek AC, Lamont JD, Goble JM, Erlichman C, James CD, Sarkaria JN | title = Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells | journal = Neoplasia | location = New York, N.Y. | volume = 7 | issue = 10 | pages = 921–929 | date = October 2005 | pmid = 16242075 | pmc = 1502028 | doi = 10.1593/neo.05361 }}{{cite journal | vauthors = Eguchi S, Tokunaga C, Hidayat S, Oshiro N, Yoshino K, Kikkawa U, Yonezawa K | title = Different 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 | journal = Genes to Cells | volume = 11 | issue = 7 | pages = 757–766 | date = July 2006 | pmid = 16824195 | doi = 10.1111/j.1365-2443.2006.00977.x | s2cid = 30113895 }}{{cite journal | vauthors = Yang D, Brunn GJ, Lawrence JC | title = Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR | journal = FEBS Letters | volume = 453 | issue = 3 | pages = 387–390 | date = June 1999 | pmid = 10405182 | doi = 10.1016/s0014-5793(99)00762-0 | s2cid = 5023204 | doi-access = free | bibcode = 1999FEBSL.453..387Y }}{{cite journal | vauthors = Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG | title = Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors | journal = European Journal of Biochemistry | volume = 269 | issue = 12 | pages = 3076–3085 | date = June 2002 | pmid = 12071973 | doi = 10.1046/j.1432-1033.2002.02992.x | doi-access = free }}{{cite journal | vauthors = Kumar V, Sabatini D, Pandey P, Gingras AC, Majumder PK, Kumar M, Yuan ZM, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S | title = Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase | journal = Journal of Biological Chemistry | volume = 275 | issue = 15 | pages = 10779–10787 | date = April 2000 | pmid = 10753870 | doi = 10.1074/jbc.275.15.10779 | doi-access = free }}{{cite journal | vauthors = Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S | title = Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation | journal = The EMBO Journal | volume = 19 | issue = 5 | pages = 1087–1097 | date = March 2000 | pmid = 10698949 | pmc = 305647 | doi = 10.1093/emboj/19.5.1087 }}{{cite journal | vauthors = Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N | title = Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism | journal = Genes & Development | volume = 13 | issue = 11 | pages = 1422–1437 | date = June 1999 | pmid = 10364159 | pmc = 316780 | doi = 10.1101/gad.13.11.1422 }}{{cite journal | vauthors = Shen X, Tomoo K, Uchiyama S, Kobayashi Y, Ishida T | title = Structural and thermodynamic behavior of eukaryotic initiation factor 4E in supramolecular formation with 4E-binding protein 1 and mRNA cap analogue, studied by spectroscopic methods | journal = Chemical & Pharmaceutical Bulletin | volume = 49 | issue = 10 | pages = 1299–1303 | date = October 2001 | pmid = 11605658 | doi = 10.1248/cpb.49.1299 | doi-access = free }}{{cite journal | vauthors = Adegoke OA, Chevalier S, Morais JA, Gougeon R, Kimball SR, Jefferson LS, Wing SS, Marliss EB | title = Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 296 | issue = 1 | pages = E105–E113 | date = January 2009 | pmid = 18957614 | pmc = 2636991 | doi = 10.1152/ajpendo.90752.2008 }}
EIF4EBP2,{{cite journal | vauthors = Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Sonenberg N | title = Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function | journal = Nature | volume = 371 | issue = 6500 | pages = 762–767 | date = October 1994 | pmid = 7935836 | doi = 10.1038/371762a0 | bibcode = 1994Natur.371..762P | s2cid = 4360955 }}
EIF4EBP3,{{cite journal | vauthors = Kleijn M, Scheper GC, Wilson ML, Tee AR, Proud CG | title = Localisation and regulation of the eIF4E-binding protein 4E-BP3 | journal = FEBS Letters | volume = 532 | issue = 3 | pages = 319–323 | date = December 2002 | pmid = 12482586 | doi = 10.1016/s0014-5793(02)03694-3 | bibcode = 2002FEBSL.532..319K | s2cid = 24527449 }}{{cite journal | vauthors = Poulin F, Gingras AC, Olsen H, Chevalier S, Sonenberg N | title = 4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family | journal = Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 14002–14007 | date = May 1998 | pmid = 9593750 | doi = 10.1074/jbc.273.22.14002 | doi-access = free }}
EIF4ENIF1,{{cite journal | vauthors = Dostie J, Ferraiuolo M, Pause A, Adam SA, Sonenberg N | title = A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5' cap-binding protein, eIF4E | journal = The EMBO Journal | volume = 19 | issue = 12 | pages = 3142–3156 | date = June 2000 | pmid = 10856257 | pmc = 203362 | doi = 10.1093/emboj/19.12.3142 }}
EIF4G1,{{cite journal | vauthors = Vary TC, Jefferson LS, Kimball SR | title = Amino acid-induced stimulation of translation initiation in rat skeletal muscle | journal = The American Journal of Physiology | volume = 277 | issue = 6 | pages = E1077–E1086 | date = December 1999 | pmid = 10600798 | doi = 10.1152/ajpendo.1999.277.6.E1077 | s2cid = 4516850 }}{{cite journal | vauthors = Harris TE, Chi A, Shabanowitz J, Hunt DF, Rhoads RE, Lawrence JC | title = mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin | journal = The EMBO Journal | volume = 25 | issue = 8 | pages = 1659–1668 | date = April 2006 | pmid = 16541103 | pmc = 1440840 | doi = 10.1038/sj.emboj.7601047 }} and
EIF4G2.{{cite journal | vauthors = Gradi A, Imataka H, Svitkin YV, Rom E, Raught B, Morino S, Sonenberg N | title = A novel functional human eukaryotic translation initiation factor 4G | journal = Molecular and Cellular Biology | volume = 18 | issue = 1 | pages = 334–342 | date = January 1998 | pmid = 9418880 | pmc = 121501 | doi = 10.1128/mcb.18.1.334 }}

{{Div col end}}. Other direct interactors: PML; arenavirus Z protein; Importin 8; potyvirus VPg protein, LRPPRC, RNMT{{Cite journal | vauthors = Osborne MJ, Volpon L, Memarpoor-Yazdi M, Pillay S, Thambipillai A, Czarnota S, Culjkovic-Kraljacic B, Trahan C, Oeffinger M, Cowling VH, Borden KL | title = Identification and Characterization of the Interaction Between the Methyl-7-Guanosine Cap Maturation Enzyme RNMT and the Cap-Binding Protein eIF4E | journal = Journal of Molecular Biology | volume = 434 | issue = 5 | pages = 167451 | date = March 2022 | pmid = 35026230 | pmc = 9288840 | doi = 10.1016/j.jmb.2022.167451 | language = en }} and others.

References

External links

[http://www.nature.com/nrmicro/journal/v5/n1/box/nrmicro1558_BX1.html Cap-dependent translation initiation] from Nature Reviews Microbiology. A good image and overview of the function of initiation factors.