Affinage

EIF4E

Eukaryotic translation initiation factor 4E · UniProt P06730

Length
217 aa
Mass
25.1 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF4E is the m7G cap-binding subunit that nucleates eIF4F-dependent ribosome recruitment, and its dosage sets the translational ceiling for a specific subset of mRNAs that drives cell growth and oncogenic transformation (PMID:12080086, PMID:26095252). Its assembly into active eIF4F is gated by competitive binding partners: 4E-BPs sequester eIF4E away from the eIF4G scaffold under low-mTOR/PI3K-Akt signaling, while related repressors that mimic the eIF4G-binding motif — Maskin in the Xenopus cell cycle and CYFIP1 in migration — likewise occlude eIF4E to silence target mRNAs such as cyclin B1 and vimentin (PMID:10216943, PMID:17086181, PMID:25588502, PMID:26824022). eIF4E is independently regulated by MNK1/2-mediated phosphorylation at Ser209 downstream of ERK/p38 MAPK; this phosphorylation tunes selective rather than global translation, driving the EMT/metastasis program (Snail, Mmp-3, NGFR), oncogenic MYC and ATF4/integrated-stress-response outputs, and neuropsychiatric and antidepressant responses, as shown by phospho-site-null knock-in mice (PMID:24909168, PMID:29367404, PMID:33690225, PMID:33135632, PMID:36274088). Sumoylation of eIF4E promotes eIF4F assembly and its pro-proliferative, anti-apoptotic output (PMID:20224576). Beyond translation, nuclear eIF4E carries out mRNA-export-dependent functions: it promotes NBS1 mRNA export for Akt-mediated survival, physically engages the CPSF 3'-end cleavage/polyadenylation machinery, and elevates splice factors (SF3B1, U2AF1) to reprogram alternative splicing in AML (PMID:18391071, PMID:31042468, PMID:36843541). In the cytoplasm, eIF4E partitions into P bodies through eIF4E-transporter (eIF4E-T) together with Lsm1 and Rck/p54 to form repressive mRNP granules that sequester developmental transcripts in neural precursors and oocytes (PMID:15840819, PMID:25456498, PMID:37218508). A noncanonical, translation-independent mitochondrial pool of eIF4E binds and represses ALDH1B1 to promote ferroptosis (PMID:36274088). The cap-binding pocket is pharmacologically tractable, with a covalent inhibitor targeting Lys162 demonstrating cellular activity (PMID:32105459).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1999 High

    Established the dual regulatory logic of eIF4E: MNK-dependent Ser209 phosphorylation versus 4E-BP sequestration relieved by PI3K-Akt-mTOR signaling, placing eIF4E at the convergence of growth and stress pathways.

    Evidence Biochemical kinase-pathway and 4E-BP binding analyses

    PMID:10216943

    Open questions at the time
    • Did not resolve the functional consequence of Ser209 phosphorylation on cap affinity
    • Did not identify mRNA targets selectively controlled
  2. 2002 High

    Connected eIF4E to mTOR-controlled cell growth, showing eIF4E and 4E-BP1 set cell size downstream of mTOR independently of S6K1.

    Evidence Rapamycin-resistant mTOR rescue, dominant-active 4E-BP1, and eIF4E overexpression with cell-size readouts

    PMID:12080086

    Open questions at the time
    • Mechanism linking eIF4E activity to size at the mRNA level unresolved
  3. 2002 Medium

    Revised the structural model of Ser209 phosphorylation, showing it cannot form the proposed salt bridge and actually lowers cap/RNA affinity, redirecting thinking toward selective rather than affinity-enhancing roles.

    Evidence Structural and biophysical binding analysis

    PMID:12423333

    Open questions at the time
    • Single analysis paper revising prior model
    • Functional output of reduced affinity not directly tested in cells
  4. 2005 High

    Defined a cytoplasmic repressive localization for eIF4E, showing eIF4E-T recruits eIF4E into P bodies alongside decay/repression machinery.

    Evidence FRET, fluorescence microscopy, and RNAi epistasis in cells

    PMID:15840819

    Open questions at the time
    • mRNA targets repressed in P bodies not identified here
    • Signals controlling P-body partitioning unknown
  5. 2006 High

    Demonstrated competitive eIF4G-mimicry as a repression mechanism, with Maskin gating cyclin B1 translation under CDK1/calcineurin control during the cell cycle.

    Evidence In vitro binding, kinase/phosphatase manipulation, and Xenopus cell-cycle translation assays

    PMID:17086181

    Open questions at the time
    • Generality of the motif-mimicry mechanism to mammalian repressors not addressed here
  6. 2008 High

    Separated eIF4E's nuclear mRNA-export activity from translation, showing export-competent W73A eIF4E rescues survival via NBS1-Akt and is antagonized by PML.

    Evidence Domain-separation mutant, survival rescue, NBS1 export assays, PML epistasis

    PMID:18391071

    Open questions at the time
    • Full set of export-dependent target mRNAs not catalogued
    • Mechanism of nuclear export selectivity unresolved
  7. 2010 Medium

    Identified sumoylation as a PTM that promotes active eIF4F assembly and is required for eIF4E's oncogenic, anti-apoptotic translational output.

    Evidence SUMO1 conjugation, eIF4F assembly, and translation/apoptosis assays with sumoylation-deficient mutant

    PMID:20224576

    Open questions at the time
    • Single lab study
    • SUMO acceptor site interplay with phosphorylation not defined
  8. 2013 Medium

    Clarified crosstalk between the two regulatory arms, showing hypophosphorylated 4E-BP restrains eIF4E phosphorylation by sequestering it from the eIF4G-MNK subcomplex.

    Evidence eIF4G/4E-BP knockdown and mTOR inhibition with phosphorylation readouts

    PMID:26824022

    Open questions at the time
    • Single lab
    • Quantitative contribution of this route in vivo unresolved
  9. 2013 Medium

    Explained the paradoxical rapamycin-induced rise in eIF4E phosphorylation through Mnk2a activation at a novel Ser437 site.

    Evidence Rapamycin treatment, isoform-specific knockdown, and Ser437 mutagenesis

    PMID:23831578

    Open questions at the time
    • Single lab
    • Upstream regulator of Mnk2a Ser437 not identified
  10. 2014 High

    Established phospho-eIF4E as a driver of metastasis, selectively translating Snail and Mmp-3 to promote EMT, with phospho-null mice resistant to lung metastasis.

    Evidence Phospho-eIF4E knock-in mouse, polysome profiling, and metastasis assays

    PMID:24909168

    Open questions at the time
    • Full phospho-eIF4E translatome not defined here
  11. 2014 High

    Extended eIF4E-T-dependent repression to development, showing eIF4E1/4E-T/P-body granules sequester proneurogenic mRNAs to maintain neural precursors.

    Evidence Reciprocal Co-IP, RIP-seq, RNAi, and neurogenesis assays in mouse cortex

    PMID:25456498

    Open questions at the time
    • Trigger for granule release during differentiation not defined
  12. 2014 Medium

    Implicated PRMT5 as required for eIF4E engagement of specific oncogenic 5'-UTRs (HIF-1α, c-Myc, cyclin D1).

    Evidence RIP, PRMT5 knockdown, and eIF4E overexpression rescue

    PMID:25234597

    Open questions at the time
    • Single lab
    • Molecular basis of how PRMT5 facilitates eIF4E-mRNA binding unresolved
  13. 2015 High

    Demonstrated eIF4E dosage selectivity: half-normal eIF4E supports normal development and global synthesis but blocks transformation by failing to translate ROS-regulating, 5'-UTR-defined mRNAs.

    Evidence Haploinsufficient mouse, ribosome profiling, and in vivo tumor models

    PMID:26095252

    Open questions at the time
    • Cis-element defining the dose-sensitive 5'-UTR signature not fully mapped
  14. 2015 Medium

    Defined a mechanism for phospho-eIF4E-driven migration: Ser209 phosphorylation releases CYFIP1 from eIF4E, relieving FMRP repression of metastasis mRNAs like vimentin.

    Evidence Mnk1/2 knockout, Mnk inhibitor, eIF4E-CYFIP1 Co-IP, and migration assays

    PMID:25588502

    Open questions at the time
    • Single lab
    • Direct structural basis of CYFIP1 release not shown
  15. 2016 Medium

    Linked eIF4E activity to targeted therapy response, showing BRAF inhibition acts through 4E-BP1-mediated eIF4E sequestration and that increasing eIF4E confers vemurafenib resistance.

    Evidence Cap-binding, polysome profiling, and 4E-BP knockdown in BRAF(V600E) melanoma

    PMID:25615552

    Open questions at the time
    • Single lab
    • Specific resistance-driving translated mRNAs not identified
  16. 2017 Medium

    Identified MST1 as a non-MNK eIF4E kinase whose phosphorylation weakens cap binding while shifting polysome association toward lncRNAs.

    Evidence In vitro kinase, cap-binding, and polysome/RIP assays

    PMID:28487214

    Open questions at the time
    • Single lab
    • Physiological context of MST1-eIF4E signaling undefined
  17. 2017 High

    Resolved eIF4E's role in cap-independent viral translation, showing it enhances eIF4F-IRES binding and eIF4A unwinding on picornavirus IRESes.

    Evidence Reconstituted eIF4F-IRES binding and helicase assays with replicon validation

    PMID:28827335

    Open questions at the time
    • Relative contribution in infected cells not quantified
  18. 2018 High

    Uncovered a CNS role for phospho-eIF4E in mood regulation, showing Ser209-null mice have depression/anxiety phenotypes, altered serotonin, and require phospho-eIF4E for fluoxetine action.

    Evidence Phospho-eIF4E knock-in mouse, translational profiling, behavior, and electrophysiology

    PMID:29367404

    Open questions at the time
    • Cell-type origin of behavioral phenotype not dissected
  19. 2018 High

    Defined a repressor competing at eIF4E's mRNA interface, with Rbm38 blocking eIF4E-p53 mRNA binding and a disrupting peptide (Pep8) restoring p53 translation.

    Evidence Co-IP, RIP, peptide competition, molecular simulation, mutagenesis, and xenograft assays

    PMID:30591552

    Open questions at the time
    • Generality of Rbm38-style mRNA-selective repression to other transcripts unknown
  20. 2019 High

    Established a direct nuclear 3'-end processing function, showing eIF4E binds CPSF3/CPSF1 and uncleaved RNA to stimulate cleavage/polyadenylation and upregulate cleavage-complex components.

    Evidence Nuclear RIP, Co-IP with CPSF components, cleavage assays, and knockdown/overexpression

    PMID:31042468

    Open questions at the time
    • Determinants of target RNA selectivity for eIF4E-stimulated cleavage unresolved
  21. 2020 High

    Demonstrated phospho-eIF4E control of MYC/ATF4 and ISR-driven glutamine metabolism cooperating with mutant KRAS in colorectal cancer, with negligible effect on global translation.

    Evidence S209A knock-in HCT116, organoid/xenograft and Apc polyposis models, polysome profiling

    PMID:33135632

    Open questions at the time
    • Mechanism conferring 5'-UTR selectivity for MYC/ATF4 not fully defined
  22. 2020 High

    Linked phospho-eIF4E to immunotherapy response, showing it translationally controls NGFR-driven melanoma phenotype switching and that MNK-eIF4E inhibition sensitizes tumors to anti-PD-1.

    Evidence Phospho-eIF4E knock-in melanoma models, polysome profiling, immune profiling, anti-PD-1 combination

    PMID:33690225

    Open questions at the time
    • Mechanism linking NGFR translation to microenvironment remodeling incomplete
  23. 2020 High

    Placed 4E-BPs as the obligate effectors of rapid antidepressants, showing cell-type-specific 4E-BP1/2 requirements for ketamine-induced plasticity and behavior.

    Evidence Cell-type-specific conditional 4E-BP knockouts, electrophysiology, and behavioral pharmacology

    PMID:33328636

    Open questions at the time
    • Specific mRNAs derepressed by 4E-BP loss to mediate antidepressant action not identified
  24. 2020 High

    Identified an eIF4E-independent escape route, showing a subset of mRNAs switches to eIF3d cap-binding when eIF4E1 is sequestered by 4E-BP.

    Evidence Ribosome profiling under constitutive 4E-BP and eIF3d cap-pocket mutagenesis

    PMID:39107322

    Open questions at the time
    • Determinants selecting mRNAs for the eIF3d pathway not defined
  25. 2020 High

    Distinguished separable Ded1 helicase contacts for eIF4A and eIF4E, with the Ded1-eIF4E contact specifically enabling translation of structured 5'-UTR mRNAs.

    Evidence In vitro PIC assembly, Ded1 NTD mutagenesis, and polysome/growth assays in yeast

    PMID:32469309

    Open questions at the time
    • Conservation and role of a Ded1-equivalent eIF4E contact in mammals not addressed
  26. 2020 High

    Provided a druggable anchor in the cap pocket, identifying Lys162-targeting covalent arylsulfonyl fluorides as the first covalent eIF4E inhibitors with cellular activity.

    Evidence Covalent docking, cocrystal structures, binding and cellular activity assays

    PMID:32105459

    Open questions at the time
    • Selectivity across eIF4E family members and in vivo efficacy not established here
  27. 2020 Low

    Proposed eIF4E as a host factor in SARS-CoV-2 translation disrupted by emetine binding the cap pocket.

    Evidence ChIP-based viral mRNA-eIF4E interaction and molecular docking

    PMID:33711336

    Open questions at the time
    • Direct emetine-eIF4E binding shown only computationally; biochemical validation lacking
    • Single method for the interaction claim
  28. 2022 High

    Revealed a translation-independent mitochondrial function, with eIF4E binding and repressing ALDH1B1 to limit 4HNE detoxification and promote ferroptosis.

    Evidence Mass spectrometry, Co-IP, genetic and pharmacological separation of functions, in vivo ferroptosis assays

    PMID:36274088

    Open questions at the time
    • How eIF4E partitions to mitochondria and is regulated there is unknown
  29. 2023 High

    Connected nuclear eIF4E to splicing control, showing export-dependent elevation of SF3B1/U2AF1 reprograms alternative splicing in cells and AML patients.

    Evidence Nuclear RIP, export assays, mutational dissection, and RNA-seq in cell lines and AML specimens

    PMID:36843541

    Open questions at the time
    • Direct versus indirect splicing roles not fully disentangled
  30. 2023 Medium

    Extended eIF4E-CPEB-based maternal mRNA control to mammalian oocytes via the PATL2-eIF4E-CPEB1 complex regulated by PATL2 degradation.

    Evidence Co-IP, Patl2 knockout and S279D knock-in mice, phosphoproteomics, and oocyte mRNA/protein quantification

    PMID:37218508

    Open questions at the time
    • Single lab
    • Direct contribution of eIF4E versus CPEB1 to the phenotype not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How eIF4E's many context-specific outputs — nuclear export/splicing/3'-end processing, P-body repression, mitochondrial ALDH1B1 control, and selective phospho-eIF4E translation — are coordinated by a shared set of cis-elements, PTMs, and competing partners remains unresolved.
  • No unified model linking PTM state to choice between translation, export, and repression
  • 5'-UTR cis-elements defining selectivity incompletely mapped
  • Regulation of subcellular partitioning (nuclear, P-body, mitochondrial) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0045182 translation regulator activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ALDH1B1CPEB1CPSF3CYFIP1EIF4AEIF4ENIF1EIF4G1RBM38
Complex memberships
CPSF 3'-end cleavage complexP bodyPATL2-eIF4E-CPEB1 complexeIF4F

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size. Overexpression of eIF4E increases cell size, and a phosphorylation-site-defective mutant of 4EBP1 that constitutively binds eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. Rapamycin-resistant mTOR mutant rescue experiments; S6K1 and eIF4E overexpression; dominant-active 4EBP1 mutant expression; cell size measurements Genes & development High 12080086
1999 eIF4E activity is regulated by phosphorylation at Ser209 by MNK1 kinase (a substrate of ERK and p38 MAPKs), and by binding to 4E-BP family translational repressor proteins that prevent incorporation of eIF4E into active translation initiation complexes; 4E-BP inhibitory interaction is relieved by PI3K-dependent phosphorylation involving Akt/PKB and FRAP/mTOR. Biochemical analysis of kinase pathways; phosphorylation site identification; 4E-BP binding assays The international journal of biochemistry & cell biology High 10216943
2002 eIF4E is phosphorylated at Ser209 by Mnk kinases; structural data place Ser209 too far from Lys159 to form the proposed salt bridge, and biophysical studies indicate phosphorylation actually decreases the affinity of eIF4E for cap or capped RNA, contrary to the original model. Structural analysis; biophysical binding studies; in vitro and in vivo phosphorylation assays European journal of biochemistry Medium 12423333
2005 eIF4E localizes to mammalian P bodies (cytoplasmic foci enriched in 5'→3' mRNA degrading enzymes) together with eIF4E-transporter (eIF4E-T); FRET studies show eIF4E interacts with eIF4E-T and rck/p54 helicase in P bodies in vivo; RNAi knockdown of eIF4E-T, LSm1, rck/p54, and Ccr4 abolishes accumulation of eIF4E in P bodies, indicating eIF4E-T is required for eIF4E P body localization. Fluorescence microscopy; FRET; RNAi knockdown; live-cell imaging RNA (New York, N.Y.) High 15840819
2008 eIF4E overexpression promotes cellular survival through Akt activation via up-regulation of NBS1 (an upstream activator of the PI3K-Akt pathway); a translation-deficient but mRNA-export-competent mutant of eIF4E (W73A) rescues serum-deprived fibroblasts as readily as wild-type eIF4E, indicating the apoptotic rescue requires eIF4E's mRNA export activity rather than its translation function. PML suppresses Akt activation and apoptotic rescue by inhibiting eIF4E-mediated NBS1 mRNA export. eIF4E W73A mutant expression; serum starvation rescue assay; Akt activity measurements; NBS1 mRNA export assay; PML overexpression The Journal of cell biology High 18391071
2010 eIF4E is sumoylated by SUMO1; sumoylation promotes formation of the active eIF4F translation initiation complex and induces translation of a subset of proteins essential for cell proliferation and preventing apoptosis; disruption of eIF4E sumoylation inhibits eIF4E-dependent protein translation and abrogates its oncogenic and anti-apoptotic functions. SUMO1 conjugation assays; eIF4F complex formation assays; translation reporter assays; sumoylation-deficient mutant analysis; cell proliferation and apoptosis assays EMBO reports Medium 20224576
2014 eIF4E phosphorylation at Ser209 (by MNK kinases downstream of TGFβ non-canonical signaling) promotes translation of Snail and Mmp-3 mRNAs to drive epithelial-to-mesenchymal transition (EMT) and lung metastasis; mice in which eIF4E cannot be phosphorylated are resistant to lung metastases in a mammary tumor model. Phospho-eIF4E knock-in mouse model; polysome profiling; metastasis assay; EMT marker analysis; TGFβ treatment Oncogene High 24909168
2015 eIF4E haploinsufficiency (50% reduction) is compatible with normal development and global protein synthesis, but significantly impedes cellular transformation; genome-wide translational profiling revealed eIF4E dose is specifically required for translating mRNAs with a unique 5' UTR signature related to reactive oxygen species regulation, which fuels transformation and cancer cell survival. Eif4e haploinsufficient mouse generation; genome-wide translational profiling (ribosome profiling); transformation assays; in vivo tumor models Cell High 26095252
2006 Maskin (a CPEB-associated protein) competes with eIF4G for binding to eIF4E via a similar peptide motif, thereby repressing translation of CPE-containing mRNAs including cyclin B1; CDK1 phosphorylation and calcineurin dephosphorylation of Maskin control the Maskin-eIF4E interaction and hence cyclin B1 mRNA translation oscillation during early cell cycles in Xenopus. In vitro binding assays; CDK1 and calcineurin gain/loss of function; translation assays; Xenopus embryo cell cycle analysis Nature structural & molecular biology High 17086181
2014 In neural precursors, eIF4E1 forms a repressive complex with 4E-T that sequesters mRNAs encoding proneurogenic transcription factors (including bHLH factors) in P-body-like granules with Lsm1 and Rck; knockdown of eIF4E1, 4E-T, or P-body proteins causes premature neurogenesis and neural precursor depletion. Co-immunoprecipitation; RIP-seq; RNAi knockdown; immunofluorescence; neurogenesis assays in mouse embryonic cortex Neuron High 25456498
2013 Rapamycin increases eIF4E phosphorylation by activating Mnk2a (but not Mnk1), requiring a novel phosphorylation site in Mnk2a (Ser437); this provides a mechanism for the paradoxical rapamycin-induced increase in eIF4E phosphorylation in cancer cells. Rapamycin treatment; Mnk1/2 isoform-specific knockdown; Ser437 site-directed mutagenesis; eIF4E phosphorylation assays FEBS letters Medium 23831578
2015 Mnk1/2 knockout impairs MNK-phosphorylated eIF4E-dependent release of CYFIP1 from eIF4E; phospho-eIF4E disrupts CYFIP1 binding to eIF4E, relieving FMRP-mediated translational repression of metastasis-related mRNAs (including vimentin) and promoting cell migration. Mnk1/2 knockout fibroblasts; selective Mnk inhibitor (Mnk-I1); Co-IP of eIF4E-CYFIP1; vimentin mRNA and protein analysis; 2D/3D migration assays The Biochemical journal Medium 25588502
2018 Ablation of eIF4E phosphorylation at Ser209 (4Eki mice) does not impair long-term spatial or contextual memory or late LTP, but causes exaggerated inflammatory responses, reduced serotonin levels, and depression/anxiety-like behaviors; translational profiling reveals phospho-eIF4E differentially regulates translation of mRNAs linked to inflammation, extracellular matrix, pituitary hormones, and the serotonin pathway; phospho-eIF4E is required for the chronic antidepressant action of fluoxetine. Phospho-eIF4E Ser209 knock-in mouse (4Eki); unbiased translational profiling; behavioral assays; serotonin level measurements; LTP electrophysiology The Journal of neuroscience High 29367404
2017 eIF4E phosphorylated by MST1 kinase weakly interacts with the 5' cap structure and reduces translation of a subset of mRNAs, while simultaneously increasing polyribosome association with lncRNAs; this represents a novel eIF4E-regulatory kinase distinct from MNKs. In vitro kinase assay (MST1 phosphorylation of eIF4E); cap-binding assay; polysome profiling; RNA immunoprecipitation Biochimica et biophysica acta. Gene regulatory mechanisms Medium 28487214
2017 eIF4E promotes eIF4F complex binding to hepatitis A virus (HAV) IRES and stimulates eIF4A-mediated duplex unwinding on the IRES; eIF4E also promotes eIF4G cleavage by poliovirus 2A protease and increases rate of poliovirus IRES restructuring, demonstrating eIF4E-dependent and -independent mechanisms for picornavirus translation. In vitro reconstituted eIF4F-IRES binding assays; helicase unwinding assays; PV replicon assays; purified viral RNA Proceedings of the National Academy of Sciences of the United States of America High 28827335
2019 Nuclear eIF4E physically interacts with CPSF3 (the 3'-end cleavage enzyme), CPSF1, and uncleaved target RNA; eIF4E stimulates 3'-end cleavage and polyadenylation of selected RNAs and drives protein expression of multiple 3'-end core cleavage complex components (CPSF3, CPSF1, CPSF2, CPSF4, Symplekin, WDR33, FIP1L1). Nuclear RNA immunoprecipitation; Co-IP of eIF4E with CPSF components; cleavage assays; knockdown/overexpression studies; multiple validation strategies Cell reports High 31042468
2018 Rbm38 suppresses p53 translation by binding to eIF4E and preventing eIF4E from binding to p53 mRNA; a synthetic peptide (Pep8) derived from the Rbm38-eIF4E binding interface disrupts this complex, relieving translational repression and increasing p53 expression; Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E. Co-IP of Rbm38-eIF4E; RNA immunoprecipitation; peptide competition assay; molecular simulation; mutagenesis (Ser-6 substitution); p53 translation and xenograft assays Cancer research High 30591552
2020 eIF4E phosphorylation at Ser209 (by MNK1/2) drives translational control of NGFR, a critical effector of melanoma phenotype switching from proliferative to invasive state; phospho-eIF4E-deficient murine melanomas express high melanocytic antigens and show reprogrammed immunosuppressive microenvironment; MNK1/2-eIF4E axis inhibition sensitizes melanoma to anti-PD-1 immunotherapy. Phospho-eIF4E knock-in mouse melanoma models; polysome profiling; NGFR translational control assays; immune profiling; anti-PD-1 combination therapy experiments The Journal of clinical investigation High 33690225
2020 eIF4E S209 phosphorylation is required for translation of MYC and ATF4, the integrated stress response (ISR)-dependent glutamine metabolic signature, and AKT activation; phospho-eIF4E cooperates with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in colorectal cancer; eIF4E S209 phosphorylation had little impact on global translation or cap binding. EIF4E heterozygous knockin (S209A) HCT116 cells; spheroid and mouse xenograft growth assays; polysome profiling; CRC organoid growth; Apc mouse polyposis model eLife High 33135632
2020 Antidepressant actions of ketamine and (2R,6R)-HNK require 4E-BP1 and 4E-BP2 as key effectors; ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 (and to lesser extent 4E-BP1); 4E-BP2 in excitatory neurons mediates antidepressant activity, while both 4E-BPs in inhibitory neurons are required; deletion of 4E-BP2 in inhibitory neurons prevents ketamine-induced increase in hippocampal excitatory neurotransmission. Cell-type-specific 4E-BP1/4E-BP2 conditional knockout mice; forced swim test; electrophysiology; behavioral pharmacology Nature High 33328636
2022 EIF4E functions as an endogenous repressor of ALDH1B1 in mitochondria in a translation-independent manner; EIF4E-ALDH1B1 interaction limits ALDH1B1-mediated detoxification of 4-hydroxynonenal (4HNE), thereby promoting ferroptosis; this noncanonical function is distinct from eIF4E's role as an eIF4G1-interacting translation factor. Mass spectrometry; Co-IP; genetic knockdown/knockout; ALDH1B1 activity assay; ferroptosis assays in vitro and in vivo; 4EGI-1 and 4E1RCat pharmacological tools Nature communications High 36274088
2013 4E-BP (in its hypophosphorylated form) restrains eIF4E phosphorylation by sequestering eIF4E away from eIF4G-MNK sub-complex; disruption of eIF4E-eIF4G interaction (via eIF4G shutdown or mTOR inhibition releasing hypophosphorylated 4E-BP) dramatically reduces eIF4E phosphorylation independently of changes in MNK expression. eIF4G knockdown; mTOR inhibition (rapamycin); 4E-BP knockdown; eIF4E phosphorylation assays Translation Medium 26824022
2020 Under eIF4E1-inactive conditions (constitutively active 4E-BP), a subset of mRNAs releases eIF4E1 and binds instead to eIF3d via its cap-binding pocket for eIF4E-independent translation; eIF3d-dependent translation is the major mechanism enabling mRNA translation when eIF4E1 is inactive. Ribosome profiling under constitutively active 4E-BP conditions; eIF3d cap-binding pocket mutagenesis; mRNA-eIF3d association assays Nature communications High 39107322
2023 eIF4E dysregulation elevates selective splice-factor production (including SF3B1 and U2AF1) primarily via its nuclear RNA export activity, thereby reprogramming alternative splicing of ~800 transcripts in cell lines and ~4,600 transcripts in high-eIF4E AML patient specimens; eIF4E also physically interacts with the spliceosome and some pre-mRNAs, suggesting direct involvement in specific splicing events. Nuclear RNA immunoprecipitation; mRNA export assays; polysome analyses; mutational studies separating export vs. translation; RNA-seq in cell lines and AML patient specimens The EMBO journal High 36843541
2014 PRMT5 is required for the interaction between eIF4E and 5'-UTRs of HIF-1α, c-Myc, and cyclin D1 mRNAs; PRMT5 knockdown reduces c-Myc and cyclin D1 protein without affecting their mRNAs; ectopic eIF4E expression rescues cell cycle progression and proliferation in PRMT5-deficient conditions. RNA immunoprecipitation (RIP); PRMT5 knockdown; eIF4E overexpression rescue; cell cycle analysis; Western blotting for cap-dependent translation targets Biochemical and biophysical research communications Medium 25234597
2020 Ded1 helicase NTD contains separate amino acid clusters required for binding eIF4A or eIF4E; Ded1-eIF4E interaction (via NTD) is independently required for stimulation of translation of mRNAs with structured 5'UTRs and for preinitiation complex assembly on structured mRNAs in vitro; disrupting Ded1-eIF4E binding reduces polysome assembly and cell growth in yeast. In vitro binding assays; site-directed mutagenesis of Ded1 NTD; PIC assembly assay; polysome analysis; cell growth assays in yeast eLife High 32469309
2023 PATL2 couples with EIF4E and CPEB1 in immature oocytes to regulate maternal mRNA expression; germinal vesicle oocytes from Patl2-/- mice exhibit decreased maternal mRNA expression and reduced protein synthesis; PATL2 phosphorylation at S279 leads to ubiquitin-mediated proteasomal degradation of PATL2, affecting the PATL2-EIF4E-CPEB1 complex. Co-IP of PATL2-EIF4E-CPEB1; Patl2 knockout mouse; phosphoproteomics; S279D knock-in mouse; proteasome inhibitor treatment; mRNA quantification in oocytes Development (Cambridge, England) Medium 37218508
2016 Vemurafenib (BRAF inhibitor) inhibits 4E-BP1 phosphorylation, promoting 4E-BP1 binding to eIF4E and blocking mRNA translation as confirmed by cap-binding and polysome profiling analysis; cells with acquired vemurafenib resistance show highly phosphorylated 4E-BP1, impeding 4E-BP1-eIF4E association; silencing 4E-BP1/2 to increase eIF4E activity renders vemurafenib-responsive cells more resistant. Cap-binding assays; polysome profiling; 4E-BP1 phosphorylation analysis; 4E-BP1/2 siRNA knockdown; vemurafenib treatment in BRAF(V600E) melanoma cells The Journal of investigative dermatology Medium 25615552
2020 Emetine disrupts binding of SARS-CoV-2 mRNA to eIF4E (demonstrated by chromatin immunoprecipitation assay) and molecular docking suggests emetine binds to the cap-binding pocket of eIF4E similarly to m7-GTP; SARS-CoV-2 exploits ERK/MNK1/eIF4E signaling for effective replication. ChIP assay for viral mRNA-eIF4E interaction; molecular docking and molecular dynamics simulation; antiviral assays; pathway inhibition experiments Antiviral research Low 33711336
2020 Covalent docking identified arylsulfonyl fluorides that target Lys162 in eIF4E near the cap-binding site; cocrystal structures guided elaboration of compound 12, the first covalent eIF4E inhibitor with cellular activity; this demonstrates Lys162 as a targetable noncatalytic residue in the eIF4E cap-binding pocket. Covalent docking; cocrystal structure determination; in vitro binding assays; cellular activity assays Journal of the American Chemical Society High 32105459
1998 Two human eIF4E genes were characterized: EIF4E1 (contains six introns, spanning >50 kb) and EIF4E2 (intronless, a retrotransposon; two amino acid differences from EIF4E1); both genes are transcribed in human cell lines but differentially expressed; transcription initiation sites mapped by primer extension and S1 nuclease mapping. Genomic library cloning; primer extension; S1 mapping; ribonuclease protection; RT-PCR The Journal of biological chemistry Medium 9468520
2004 Mammalian eIF4E-1 (canonical) interacts with both eIF4G scaffold and 4E-BPs; eIF4E-2 (4EHP) binds cap and 4E-BPs but does NOT interact with eIF4G; eIF4E-3 interacts with eIF4G but NOT 4E-BPs; neither eIF4E-2 nor eIF4E-3 can rescue eIF4E gene deletion lethality in yeast, indicating functional specialization. Co-immunoprecipitation; cap-binding assay; yeast complementation assay; in vitro binding assays European journal of biochemistry High 15153109

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes & development 900 12080086
2004 eIF-4E expression and its role in malignancies and metastases. Oncogene 618 15094768
2004 eIF4E--from translation to transformation. Oncogene 390 15094766
2005 A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. RNA (New York, N.Y.) 321 15840819
2015 Differential Requirements for eIF4E Dose in Normal Development and Cancer. Cell 297 26095252
1999 eIF4E expression in tumors: its possible role in progression of malignancies. The international journal of biochemistry & cell biology 294 10216944
2002 Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? European journal of biochemistry 246 12423333
1999 eIF4E activity is regulated at multiple levels. The international journal of biochemistry & cell biology 246 10216943
2014 Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 218 24909168
2015 Signalling to eIF4E in cancer. Biochemical Society transactions 183 26517881
2008 eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. Biochemistry and cell biology = Biochimie et biologie cellulaire 154 18443631
2004 Characterization of mammalian eIF4E-family members. European journal of biochemistry 142 15153109
2009 eIF4E: new family members, new binding partners, new roles. The Journal of biological chemistry 128 19237539
2020 The RALF1-FERONIA Complex Phosphorylates eIF4E1 to Promote Protein Synthesis and Polar Root Hair Growth. Molecular plant 120 31904511
2020 Antidepressant actions of ketamine engage cell-specific translation via eIF4E. Nature 107 33328636
2014 Mnks, eIF4E phosphorylation and cancer. Biochimica et biophysica acta 101 25450520
2002 The emerging roles of translation factor eIF4E in the nucleus. Differentiation; research in biological diversity 101 11963652
2005 Phylogenetic analysis of eIF4E-family members. BMC evolutionary biology 100 16191198
2013 The oncogene eIF4E: using biochemical insights to target cancer. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 94 23472659
2012 Anti-oncogenic potential of the eIF4E-binding proteins. Oncogene 89 22508483
2005 Further evidence that ribavirin interacts with eIF4E. RNA (New York, N.Y.) 88 16251386
2022 A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nature communications 85 36274088
2016 Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK-eIF4E Axis. Trends in biochemical sciences 85 27527252
2001 Translational regulation in cell stress and apoptosis. Roles of the eIF4E binding proteins. Journal of cellular and molecular medicine 84 12067482
2017 eIF4E Resistance: Natural Variation Should Guide Gene Editing. Trends in plant science 83 28258958
2008 eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Molecular cancer therapeutics 83 18644990
2008 The eIF4E RNA regulon promotes the Akt signaling pathway. The Journal of cell biology 82 18391071
2014 An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron 80 25456498
2020 Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking. Journal of the American Chemical Society 77 32105459
2014 MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL. Nature communications 76 25403230
2011 Knock-down of both eIF4E1 and eIF4E2 genes confers broad-spectrum resistance against potyviruses in tomato. PloS one 72 22242134
2020 Phosphorylation of the mRNA cap-binding protein eIF4E and cancer. Cellular signalling 69 32535199
2018 Loss of eIF4E Phosphorylation Engenders Depression-like Behaviors via Selective mRNA Translation. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 29367404
2018 The Role of the Eukaryotic Translation Initiation Factor 4E (eIF4E) in Neuropsychiatric Disorders. Frontiers in genetics 68 30532767
2016 The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes. Science signaling 57 27245614
2015 The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding. The Biochemical journal 57 25588502
2003 Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. The Journal of biological chemistry 55 14607835
2020 Genome Editing of eIF4E1 in Tomato Confers Resistance to Pepper Mottle Virus. Frontiers in plant science 53 32849681
2021 Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses. The Journal of clinical investigation 52 33690225
2021 Control of the eIF4E activity: structural insights and pharmacological implications. Cellular and molecular life sciences : CMLS 49 34541613
2009 Cap in hand: targeting eIF4E. Cell cycle (Georgetown, Tex.) 49 19597330
1999 Expression of eIF4E during head and neck tumorigenesis: possible role in angiogenesis. The Laryngoscope 49 10443829
2018 eIF4E Phosphorylation in Prostate Cancer. Neoplasia (New York, N.Y.) 47 29730477
2005 Homeodomain proteins and eukaryotic translation initiation factor 4E (eIF4E): an unexpected relationship. Histology and histopathology 46 16136508
2005 Expression of the eukaryotic translation initiation factor 4E (eIF4E) and 4E-BP1 in esophageal cancer. Clinical biochemistry 46 16375881
2021 Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E. Antiviral research 45 33711336
2017 eIF4E phosphorylation by MST1 reduces translation of a subset of mRNAs, but increases lncRNA translation. Biochimica et biophysica acta. Gene regulatory mechanisms 44 28487214
2016 Distinct recruitment of human eIF4E isoforms to processing bodies and stress granules. BMC molecular biology 44 27578149
2017 Cellular cap-binding protein, eIF4E, promotes picornavirus genome restructuring and translation. Proceedings of the National Academy of Sciences of the United States of America 43 28827335
2013 Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a). FEBS letters 43 23831578
2018 eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity. Frontiers in genetics 42 30459806
2006 CDK1 and calcineurin regulate Maskin association with eIF4E and translational control of cell cycle progression. Nature structural & molecular biology 41 17086181
2018 Disruption of the Rbm38-eIF4E Complex with a Synthetic Peptide Pep8 Increases p53 Expression. Cancer research 39 30591552
2009 An eIF4E-binding protein regulates katanin protein levels in C. elegans embryos. The Journal of cell biology 39 19786575
2018 Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling. Molecular oncology 38 30221473
2019 Nuclear eIF4E Stimulates 3'-End Cleavage of Target RNAs. Cell reports 37 31042468
2015 eIF4E as a control target for viruses. Viruses 37 25690796
2010 Sumoylation of eIF4E activates mRNA translation. EMBO reports 37 20224576
2019 Eukaryotic initiation factor 4E (eIF4E): A recap of the cap-binding protein. Journal of cellular biochemistry 35 31074051
2016 Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion. The FEBS journal 35 27618366
2022 The mTOR/4E-BP1/eIF4E Signalling Pathway as a Source of Cancer Drug Targets. Current medicinal chemistry 34 35209811
2020 Distinct interactions of eIF4A and eIF4E with RNA helicase Ded1 stimulate translation in vivo. eLife 34 32469309
2018 Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia. Oncogene 34 30478448
2017 Regulation of Translation by TOR, eIF4E and eIF2α in Plants: Current Knowledge, Challenges and Future Perspectives. Frontiers in plant science 34 28491073
2017 Inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 34 28766096
2001 A second eIF4E protein in Schizosaccharomyces pombe has distinct eIF4G-binding properties. Nucleic acids research 34 11713305
2016 Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia. Cytokine 33 27094611
2022 Editing melon eIF4E associates with virus resistance and male sterility. Plant biotechnology journal 32 35778883
2020 eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis. eLife 31 33135632
2019 A novel eIF4E-interacting protein that forms non-canonical translation initiation complexes. Nature plants 31 31819221
2014 eIF4E-binding proteins: new factors, new locations, new roles. Biochemical Society transactions 31 25110031
2020 Distinct roles of two eIF4E isoforms in the germline of Caenorhabditis elegans. Journal of cell science 30 32079657
1998 Cloning and characterization of human eIF4E genes. The Journal of biological chemistry 29 9468520
2020 The MNK1/2-eIF4E Axis as a Potential Therapeutic Target in Melanoma. International journal of molecular sciences 28 32517051
2014 eIF4E-mediated translational control of cancer incidence. Biochimica et biophysica acta 28 25263391
2007 Significance of eIF4E expression in skin squamous cell carcinoma. Cell biology international 28 17689990
2023 PATL2 regulates mRNA homeostasis in oocytes by interacting with EIF4E and CPEB1. Development (Cambridge, England) 27 37218508
2018 The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 27 30530594
2017 Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 29049978
2016 Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E. Cancer research 26 27879264
2013 4E-BP restrains eIF4E phosphorylation. Translation (Austin, Tex.) 26 26824022
2011 Analysis of eIF4E and 4EBP1 mRNAs in head and neck cancer. The Laryngoscope 26 21898433
2007 Protein synthesis and aging: eIF4E and the soma vs. germline distinction. Cell cycle (Georgetown, Tex.) 26 17495543
2022 CRISPR-Cas9 Targeting of the eIF4E1 Gene Extends the Potato Virus Y Resistance Spectrum of the Solanum tuberosum L. cv. Desirée. Frontiers in microbiology 25 35722301
2021 eIF4E-homologous protein (4EHP): a multifarious cap-binding protein. The FEBS journal 25 34758096
2015 The role of eIF4E in response and acquired resistance to vemurafenib in melanoma. The Journal of investigative dermatology 24 25615552
2014 PRMT5 is essential for the eIF4E-mediated 5'-cap dependent translation. Biochemical and biophysical research communications 24 25234597
2023 Plant eIF4E isoforms as factors of susceptibility and resistance to potyviruses. Frontiers in plant science 23 36844044
2016 eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma. Oncotarget 23 27588477
2024 eIF4E-independent translation is largely eIF3d-dependent. Nature communications 22 39107322
2023 The eukaryotic translation initiation factor eIF4E reprograms alternative splicing. The EMBO journal 22 36843541
2016 eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation. Cancer letters 22 26945967
2024 eIF4E orchestrates mRNA processing, RNA export and translation to modify specific protein production. Nucleus (Austin, Tex.) 21 38880976
2023 RIPK1-dependent necroptosis promotes vasculogenic mimicry formation via eIF4E in triple-negative breast cancer. Cell death & disease 21 37217473
2020 Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer. Oncogene 21 32066877
2020 eIF4E phosphorylation modulates pain and neuroinflammation in the aged. GeroScience 21 32613493
2019 Soybean RNA interference lines silenced for eIF4E show broad potyvirus resistance. Molecular plant pathology 21 31860775
2002 Localisation and regulation of the eIF4E-binding protein 4E-BP3. FEBS letters 21 12482586
2023 Biological functions and research progress of eIF4E. Frontiers in oncology 20 37601696
2010 Direct inhibition of eIF4E reduced cell growth in endometrial adenocarcinoma. Journal of cancer research and clinical oncology 19 20464414

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