{"gene":"EIF4E","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Rapamycin-resistant mTOR mutant rescue experiments; S6K1 and eIF4E overexpression; dominant-active 4EBP1 mutant expression; cell size measurements","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic tools (rapamycin-resistant mTOR, constitutively active 4EBP1, eIF4E overexpression) with defined cellular phenotype (cell size), replicated across conditions","pmids":["12080086"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Biochemical analysis of kinase pathways; phosphorylation site identification; 4E-BP binding assays","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway placement replicated across multiple labs, supported by structural and biochemical data described across corpus","pmids":["10216943"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Structural analysis; biophysical binding studies; in vitro and in vivo phosphorylation assays","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural and biophysical data from single review/analysis paper, but negative/revised finding contradicts prior model","pmids":["12423333"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Fluorescence microscopy; FRET; RNAi knockdown; live-cell imaging","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET-validated protein interactions in vivo, RNAi functional epistasis with clear localization phenotype, multiple orthogonal methods in single study","pmids":["15840819"],"is_preprint":false},{"year":2008,"finding":"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.","method":"eIF4E W73A mutant expression; serum starvation rescue assay; Akt activity measurements; NBS1 mRNA export assay; PML overexpression","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-separation mutant (W73A) distinguishes export vs. translation activity; multiple functional readouts; epistasis with PML; single lab but orthogonal methods","pmids":["18391071"],"is_preprint":false},{"year":2010,"finding":"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.","method":"SUMO1 conjugation assays; eIF4F complex formation assays; translation reporter assays; sumoylation-deficient mutant analysis; cell proliferation and apoptosis assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified new PTM with functional consequences on eIF4F assembly and translation, but single lab study","pmids":["20224576"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Phospho-eIF4E knock-in mouse model; polysome profiling; metastasis assay; EMT marker analysis; TGFβ treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with defined phospho-site ablation, in vivo metastasis readout, and mRNA-specific translational mechanism identified; multiple orthogonal methods","pmids":["24909168"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Eif4e haploinsufficient mouse generation; genome-wide translational profiling (ribosome profiling); transformation assays; in vivo tumor models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model, genome-wide translational profiling, in vivo cancer readout, multiple orthogonal methods in single rigorous study","pmids":["26095252"],"is_preprint":false},{"year":2006,"finding":"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.","method":"In vitro binding assays; CDK1 and calcineurin gain/loss of function; translation assays; Xenopus embryo cell cycle analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic reconstitution of competitive binding to eIF4E; kinase/phosphatase regulation established biochemically and genetically; cell cycle oscillation readout in Xenopus","pmids":["17086181"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation; RIP-seq; RNAi knockdown; immunofluorescence; neurogenesis assays in mouse embryonic cortex","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, RIP-seq, and defined neurogenesis phenotype; multiple orthogonal methods in single study","pmids":["25456498"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Rapamycin treatment; Mnk1/2 isoform-specific knockdown; Ser437 site-directed mutagenesis; eIF4E phosphorylation assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis identifying Mnk2a Ser437, isoform-specific effects validated, single lab with two orthogonal methods","pmids":["23831578"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Mnk1/2 knockout fibroblasts; selective Mnk inhibitor (Mnk-I1); Co-IP of eIF4E-CYFIP1; vimentin mRNA and protein analysis; 2D/3D migration assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and pharmacological inhibition, Co-IP interaction, migration phenotype; single lab","pmids":["25588502"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Phospho-eIF4E Ser209 knock-in mouse (4Eki); unbiased translational profiling; behavioral assays; serotonin level measurements; LTP electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with precise phospho-site ablation, genome-wide translational profiling, behavioral and electrophysiological readouts; multiple orthogonal methods","pmids":["29367404"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro kinase assay (MST1 phosphorylation of eIF4E); cap-binding assay; polysome profiling; RNA immunoprecipitation","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay and polysome profiling, cap-binding measured directly; single lab","pmids":["28487214"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro reconstituted eIF4F-IRES binding assays; helicase unwinding assays; PV replicon assays; purified viral RNA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — fully reconstituted in vitro system measuring IRES binding affinity and helicase activity; multiple mechanistic readouts in single study","pmids":["28827335"],"is_preprint":false},{"year":2019,"finding":"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).","method":"Nuclear RNA immunoprecipitation; Co-IP of eIF4E with CPSF components; cleavage assays; knockdown/overexpression studies; multiple validation strategies","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNA-IP, functional cleavage assays, knockdown), identifies direct physical interaction and functional consequence; single rigorous study","pmids":["31042468"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP of Rbm38-eIF4E; RNA immunoprecipitation; peptide competition assay; molecular simulation; mutagenesis (Ser-6 substitution); p53 translation and xenograft assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — binding interface identified by Co-IP and molecular simulation with mutagenesis validation; functional translation rescue; multiple orthogonal methods","pmids":["30591552"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Phospho-eIF4E knock-in mouse melanoma models; polysome profiling; NGFR translational control assays; immune profiling; anti-PD-1 combination therapy experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic phospho-eIF4E ablation in vivo, specific downstream target (NGFR) identified translationally, immune microenvironment readout, in vivo treatment experiments","pmids":["33690225"],"is_preprint":false},{"year":2020,"finding":"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.","method":"EIF4E heterozygous knockin (S209A) HCT116 cells; spheroid and mouse xenograft growth assays; polysome profiling; CRC organoid growth; Apc mouse polyposis model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise genetic knock-in (S209A), multiple in vitro and in vivo cancer models, translational profiling; multiple orthogonal methods","pmids":["33135632"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Cell-type-specific 4E-BP1/4E-BP2 conditional knockout mice; forced swim test; electrophysiology; behavioral pharmacology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockouts, electrophysiological and behavioral readouts, multiple 4E-BP isoforms and cell types examined; rigorous study in Nature","pmids":["33328636"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mass spectrometry; Co-IP; genetic knockdown/knockout; ALDH1B1 activity assay; ferroptosis assays in vitro and in vivo; 4EGI-1 and 4E1RCat pharmacological tools","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry-identified interaction, genetic and pharmacological separation of translation-dependent and -independent functions, in vivo validation; multiple orthogonal methods","pmids":["36274088"],"is_preprint":false},{"year":2013,"finding":"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.","method":"eIF4G knockdown; mTOR inhibition (rapamycin); 4E-BP knockdown; eIF4E phosphorylation assays","journal":"Translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic disruption of eIF4G-eIF4E interaction with defined phosphorylation readout; single lab, two orthogonal approaches","pmids":["26824022"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Ribosome profiling under constitutively active 4E-BP conditions; eIF3d cap-binding pocket mutagenesis; mRNA-eIF3d association assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ribosome profiling with constitutively active 4E-BP genetic tool; eIF3d cap-binding mutant; mechanistic alternative pathway established; multiple orthogonal methods","pmids":["39107322"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Nuclear RNA immunoprecipitation; mRNA export assays; polysome analyses; mutational studies separating export vs. translation; RNA-seq in cell lines and AML patient specimens","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (nuclear RIP, export assays, polysome profiling, mutational dissection), validated in patient specimens; single lab but comprehensive mechanistic study","pmids":["36843541"],"is_preprint":false},{"year":2014,"finding":"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.","method":"RNA immunoprecipitation (RIP); PRMT5 knockdown; eIF4E overexpression rescue; cell cycle analysis; Western blotting for cap-dependent translation targets","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP assay and epistasis rescue experiment; single lab, limited mechanistic detail on how PRMT5 facilitates eIF4E-mRNA interaction","pmids":["25234597"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro binding assays; site-directed mutagenesis of Ded1 NTD; PIC assembly assay; polysome analysis; cell growth assays in yeast","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of PIC assembly, site-directed mutagenesis separating Ded1-eIF4A vs. Ded1-eIF4E binding, multiple functional readouts; rigorous study","pmids":["32469309"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP of PATL2-EIF4E-CPEB1; Patl2 knockout mouse; phosphoproteomics; S279D knock-in mouse; proteasome inhibitor treatment; mRNA quantification in oocytes","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies complex, two genetic mouse models (KO and knock-in), multiple readouts; single lab","pmids":["37218508"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Cap-binding assays; polysome profiling; 4E-BP1 phosphorylation analysis; 4E-BP1/2 siRNA knockdown; vemurafenib treatment in BRAF(V600E) melanoma cells","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cap-binding and polysome profiling directly measure eIF4E activity; 4E-BP epistasis established; single lab","pmids":["25615552"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ChIP assay for viral mRNA-eIF4E interaction; molecular docking and molecular dynamics simulation; antiviral assays; pathway inhibition experiments","journal":"Antiviral research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP assay for interaction and computational docking; limited biochemical validation of emetine-eIF4E direct binding; single lab, single method for direct binding claim","pmids":["33711336"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Covalent docking; cocrystal structure determination; in vitro binding assays; cellular activity assays","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cocrystal structures with functional validation, covalent inhibitor with cellular activity, identifies specific lysine residue; rigorous structural and chemical biology study","pmids":["32105459"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Genomic library cloning; primer extension; S1 mapping; ribonuclease protection; RT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization with multiple mapping methods; established gene structure and differential expression","pmids":["9468520"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Co-immunoprecipitation; cap-binding assay; yeast complementation assay; in vitro binding assays","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple binding assays (Co-IP, cap binding, yeast complementation) across three family members; clearly distinguishes differential protein-protein interactions; single lab but multiple orthogonal methods","pmids":["15153109"],"is_preprint":false}],"current_model":"EIF4E is the rate-limiting mRNA 5' m7G cap-binding protein that nucleates the eIF4F complex (with eIF4G and eIF4A) to recruit ribosomes to mRNAs; its activity is regulated by competitive binding of 4E-BPs (controlled by mTOR-dependent phosphorylation), by phosphorylation at Ser209 by MNK1/2 kinases (downstream of ERK/p38 MAPK) which modulates selective mRNA translation rather than global rates, and by sumoylation; in the nucleus, eIF4E promotes export of specific mRNAs, stimulates 3'-end cleavage/polyadenylation, and reprograms alternative splicing by upregulating splice factors; in the cytoplasm, eIF4E localizes to P bodies via eIF4E-T and represses translation of specific mRNAs in developmental contexts; phospho-eIF4E selectively drives translation of mRNAs governing metastasis (Snail, Mmp-3), oncogenesis (Myc, ATF4), neuropsychiatric responses, and pain plasticity, while a noncanonical mitochondrial function of EIF4E represses ALDH1B1 to promote ferroptosis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1999,"claim":"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","pmids":["10216943"],"confidence":"High","gaps":["Did not resolve the functional consequence of Ser209 phosphorylation on cap affinity","Did not identify mRNA targets selectively controlled"]},{"year":2002,"claim":"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","pmids":["12080086"],"confidence":"High","gaps":["Mechanism linking eIF4E activity to size at the mRNA level unresolved"]},{"year":2002,"claim":"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","pmids":["12423333"],"confidence":"Medium","gaps":["Single analysis paper revising prior model","Functional output of reduced affinity not directly tested in cells"]},{"year":2005,"claim":"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","pmids":["15840819"],"confidence":"High","gaps":["mRNA targets repressed in P bodies not identified here","Signals controlling P-body partitioning unknown"]},{"year":2006,"claim":"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","pmids":["17086181"],"confidence":"High","gaps":["Generality of the motif-mimicry mechanism to mammalian repressors not addressed here"]},{"year":2008,"claim":"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","pmids":["18391071"],"confidence":"High","gaps":["Full set of export-dependent target mRNAs not catalogued","Mechanism of nuclear export selectivity unresolved"]},{"year":2010,"claim":"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","pmids":["20224576"],"confidence":"Medium","gaps":["Single lab study","SUMO acceptor site interplay with phosphorylation not defined"]},{"year":2013,"claim":"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","pmids":["26824022"],"confidence":"Medium","gaps":["Single lab","Quantitative contribution of this route in vivo unresolved"]},{"year":2013,"claim":"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","pmids":["23831578"],"confidence":"Medium","gaps":["Single lab","Upstream regulator of Mnk2a Ser437 not identified"]},{"year":2014,"claim":"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","pmids":["24909168"],"confidence":"High","gaps":["Full phospho-eIF4E translatome not defined here"]},{"year":2014,"claim":"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","pmids":["25456498"],"confidence":"High","gaps":["Trigger for granule release during differentiation not defined"]},{"year":2014,"claim":"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","pmids":["25234597"],"confidence":"Medium","gaps":["Single lab","Molecular basis of how PRMT5 facilitates eIF4E-mRNA binding unresolved"]},{"year":2015,"claim":"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","pmids":["26095252"],"confidence":"High","gaps":["Cis-element defining the dose-sensitive 5'-UTR signature not fully mapped"]},{"year":2015,"claim":"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","pmids":["25588502"],"confidence":"Medium","gaps":["Single lab","Direct structural basis of CYFIP1 release not shown"]},{"year":2016,"claim":"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","pmids":["25615552"],"confidence":"Medium","gaps":["Single lab","Specific resistance-driving translated mRNAs not identified"]},{"year":2017,"claim":"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","pmids":["28487214"],"confidence":"Medium","gaps":["Single lab","Physiological context of MST1-eIF4E signaling undefined"]},{"year":2017,"claim":"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","pmids":["28827335"],"confidence":"High","gaps":["Relative contribution in infected cells not quantified"]},{"year":2018,"claim":"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","pmids":["29367404"],"confidence":"High","gaps":["Cell-type origin of behavioral phenotype not dissected"]},{"year":2018,"claim":"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","pmids":["30591552"],"confidence":"High","gaps":["Generality of Rbm38-style mRNA-selective repression to other transcripts unknown"]},{"year":2019,"claim":"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","pmids":["31042468"],"confidence":"High","gaps":["Determinants of target RNA selectivity for eIF4E-stimulated cleavage unresolved"]},{"year":2020,"claim":"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","pmids":["33135632"],"confidence":"High","gaps":["Mechanism conferring 5'-UTR selectivity for MYC/ATF4 not fully defined"]},{"year":2020,"claim":"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","pmids":["33690225"],"confidence":"High","gaps":["Mechanism linking NGFR translation to microenvironment remodeling incomplete"]},{"year":2020,"claim":"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","pmids":["33328636"],"confidence":"High","gaps":["Specific mRNAs derepressed by 4E-BP loss to mediate antidepressant action not identified"]},{"year":2020,"claim":"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","pmids":["39107322"],"confidence":"High","gaps":["Determinants selecting mRNAs for the eIF3d pathway not defined"]},{"year":2020,"claim":"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","pmids":["32469309"],"confidence":"High","gaps":["Conservation and role of a Ded1-equivalent eIF4E contact in mammals not addressed"]},{"year":2020,"claim":"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","pmids":["32105459"],"confidence":"High","gaps":["Selectivity across eIF4E family members and in vivo efficacy not established here"]},{"year":2020,"claim":"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","pmids":["33711336"],"confidence":"Low","gaps":["Direct emetine-eIF4E binding shown only computationally; biochemical validation lacking","Single method for the interaction claim"]},{"year":2022,"claim":"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","pmids":["36274088"],"confidence":"High","gaps":["How eIF4E partitions to mitochondria and is regulated there is unknown"]},{"year":2023,"claim":"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","pmids":["36843541"],"confidence":"High","gaps":["Direct versus indirect splicing roles not fully disentangled"]},{"year":2023,"claim":"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","pmids":["37218508"],"confidence":"Medium","gaps":["Single lab","Direct contribution of eIF4E versus CPEB1 to the phenotype not separated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,15,23,24]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,7,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,11,16,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,15,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,17,18,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[20]}],"complexes":["eIF4F","P body","PATL2-eIF4E-CPEB1 complex","CPSF 3'-end cleavage complex"],"partners":["EIF4G1","EIF4A","EIF4ENIF1","CYFIP1","CPSF3","RBM38","ALDH1B1","CPEB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06730","full_name":"Eukaryotic translation initiation factor 4E","aliases":["eIF-4F 25 kDa subunit","mRNA cap-binding protein"],"length_aa":217,"mass_kda":25.1,"function":"Acts in the cytoplasm to initiate and regulate protein synthesis and is required in the nucleus for export of a subset of mRNAs from the nucleus to the cytoplasm which promotes processes such as RNA capping, processing and splicing (PubMed:11606200, PubMed:22578813, PubMed:22684010, PubMed:24335285, PubMed:29987188). Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (By similarity). This protein recognizes and binds the 7-methylguanosine (m7G)-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures (PubMed:16271312, PubMed:22578813). Together with EIF4G1, antagonizes the scanning promoted by EIF1-EIF4G1 and is required for TISU translation, a process where the TISU element recognition makes scanning unnecessary (PubMed:29987188). In addition to its role in translation initiation, also acts as a regulator of translation and stability in the cytoplasm (PubMed:24335285). Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression: in the complex, EIF4E mediates the binding to the mRNA cap (By similarity). Component of a multiprotein complex that sequesters and represses translation of proneurogenic factors during neurogenesis (By similarity). In P-bodies, component of a complex that mediates the storage of translationally inactive mRNAs in the cytoplasm and prevents their degradation (PubMed:24335285). May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). As well as its roles in translation, also involved in mRNA nucleocytoplasmic transport (By similarity). Its role in mRNA export from the nucleus to the cytoplasm relies on its ability to bind the m7G cap of RNAs and on the presence of the 50-nucleotide EIF4E sensitivity element (4ESE) in the 3'UTR of sensitive transcripts (By similarity). Interaction with the 4ESE is mediated by LRPPRC which binds simultaneously to both EIF4E and the 4ESE, thereby acting as a platform for assembly for the RNA export complex (By similarity). EIF4E-dependent mRNA export is independent of ongoing protein or RNA synthesis and is also NFX1-independent but is XPO1-dependent with LRPPRC interacting with XPO1 to form an EIF4E-dependent mRNA export complex (By similarity). Alters the composition of the cytoplasmic face of the nuclear pore to promote RNA export by reducing RANBP2 expression, relocalizing nucleoporin NUP214 and increasing expression of RANBP1 and RNA export factors DDX19 and GLE1 (By similarity). Promotes the nuclear export of cyclin CCND1 mRNA (By similarity). Promotes the nuclear export of NOS2/iNOS mRNA (PubMed:23471078). Promotes the nuclear export of MDM2 mRNA (PubMed:22684010). Promotes the export of additional mRNAs, including others involved in the cell cycle (By similarity). In the nucleus, binds to capped splice factor-encoding mRNAs and stimulates their nuclear export to enhance splice factor production by increasing their cytoplasmic availability to the translation machinery (By similarity). May also regulate splicing through interaction with the spliceosome in an RNA and m7G cap-dependent manner (By similarity). Also binds to some pre-mRNAs and may play a role in their recruitment to the spliceosome (By similarity). Promotes steady-state capping of a subset of coding and non-coding RNAs by mediating nuclear export of capping machinery mRNAs including RNMT, RNGTT and RAMAC to enhance their translation (By similarity). Stimulates mRNA 3'-end processing by promoting the expression of several core cleavage complex factors required for mRNA cleavage and polyadenylation, and may also have a direct effect through its interaction with the CPSF3 cleavage enzyme (By similarity). Rescues cells from apoptosis by promoting activation of serine/threonine-protein kinase AKT1 through mRNA export of NBS1 which potentiates AKT1 phosphorylation and also through mRNA export of AKT1 effectors, allowing for increased production of these proteins (By similarity)","subcellular_location":"Cytoplasm, P-body; Cytoplasm; Cytoplasm, Stress granule; Nucleus; Nucleus speckle; Nucleus, nuclear body","url":"https://www.uniprot.org/uniprotkb/P06730/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF4E","classification":"Common Essential","n_dependent_lines":1200,"n_total_lines":1208,"dependency_fraction":0.9933774834437086},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"WDR3","stoichiometry":10.0},{"gene":"EIF3B","stoichiometry":4.0},{"gene":"EIF4A1","stoichiometry":4.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"ATG4B","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CASP3","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF4E","total_profiled":1310},"omim":[{"mim_id":"619901","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 1; EIF1","url":"https://www.omim.org/entry/619901"},{"mim_id":"619537","title":"ANGEL HOMOLOG 1; ANGEL1","url":"https://www.omim.org/entry/619537"},{"mim_id":"615091","title":"AUTISM, SUSCEPTIBILITY TO, 19; AUTS19","url":"https://www.omim.org/entry/615091"},{"mim_id":"610777","title":"NEUROGUIDIN; NGDN","url":"https://www.omim.org/entry/610777"},{"mim_id":"610252","title":"MICRO RNA 1-2; MIR1-2","url":"https://www.omim.org/entry/610252"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF4E"},"hgnc":{"alias_symbol":["EIF4E1"],"prev_symbol":["EIF4EL1","EIF4F"]},"alphafold":{"accession":"P06730","domains":[{"cath_id":"3.30.760.10","chopping":"36-215","consensus_level":"medium","plddt":96.9308,"start":36,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06730","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06730-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06730-F1-predicted_aligned_error_v6.png","plddt_mean":90.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF4E","jax_strain_url":"https://www.jax.org/strain/search?query=EIF4E"},"sequence":{"accession":"P06730","fasta_url":"https://rest.uniprot.org/uniprotkb/P06730.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06730/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06730"}},"corpus_meta":[{"pmid":"12080086","id":"PMC_12080086","title":"Mammalian cell 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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.\",\n      \"method\": \"Rapamycin-resistant mTOR mutant rescue experiments; S6K1 and eIF4E overexpression; dominant-active 4EBP1 mutant expression; cell size measurements\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic tools (rapamycin-resistant mTOR, constitutively active 4EBP1, eIF4E overexpression) with defined cellular phenotype (cell size), replicated across conditions\",\n      \"pmids\": [\"12080086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical analysis of kinase pathways; phosphorylation site identification; 4E-BP binding assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway placement replicated across multiple labs, supported by structural and biochemical data described across corpus\",\n      \"pmids\": [\"10216943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Structural analysis; biophysical binding studies; in vitro and in vivo phosphorylation assays\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and biophysical data from single review/analysis paper, but negative/revised finding contradicts prior model\",\n      \"pmids\": [\"12423333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy; FRET; RNAi knockdown; live-cell imaging\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-validated protein interactions in vivo, RNAi functional epistasis with clear localization phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15840819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"eIF4E W73A mutant expression; serum starvation rescue assay; Akt activity measurements; NBS1 mRNA export assay; PML overexpression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-separation mutant (W73A) distinguishes export vs. translation activity; multiple functional readouts; epistasis with PML; single lab but orthogonal methods\",\n      \"pmids\": [\"18391071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"SUMO1 conjugation assays; eIF4F complex formation assays; translation reporter assays; sumoylation-deficient mutant analysis; cell proliferation and apoptosis assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified new PTM with functional consequences on eIF4F assembly and translation, but single lab study\",\n      \"pmids\": [\"20224576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-eIF4E knock-in mouse model; polysome profiling; metastasis assay; EMT marker analysis; TGFβ treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with defined phospho-site ablation, in vivo metastasis readout, and mRNA-specific translational mechanism identified; multiple orthogonal methods\",\n      \"pmids\": [\"24909168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Eif4e haploinsufficient mouse generation; genome-wide translational profiling (ribosome profiling); transformation assays; in vivo tumor models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model, genome-wide translational profiling, in vivo cancer readout, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"26095252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays; CDK1 and calcineurin gain/loss of function; translation assays; Xenopus embryo cell cycle analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic reconstitution of competitive binding to eIF4E; kinase/phosphatase regulation established biochemically and genetically; cell cycle oscillation readout in Xenopus\",\n      \"pmids\": [\"17086181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; RIP-seq; RNAi knockdown; immunofluorescence; neurogenesis assays in mouse embryonic cortex\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, RIP-seq, and defined neurogenesis phenotype; multiple orthogonal methods in single study\",\n      \"pmids\": [\"25456498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Rapamycin treatment; Mnk1/2 isoform-specific knockdown; Ser437 site-directed mutagenesis; eIF4E phosphorylation assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis identifying Mnk2a Ser437, isoform-specific effects validated, single lab with two orthogonal methods\",\n      \"pmids\": [\"23831578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Mnk1/2 knockout fibroblasts; selective Mnk inhibitor (Mnk-I1); Co-IP of eIF4E-CYFIP1; vimentin mRNA and protein analysis; 2D/3D migration assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and pharmacological inhibition, Co-IP interaction, migration phenotype; single lab\",\n      \"pmids\": [\"25588502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-eIF4E Ser209 knock-in mouse (4Eki); unbiased translational profiling; behavioral assays; serotonin level measurements; LTP electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with precise phospho-site ablation, genome-wide translational profiling, behavioral and electrophysiological readouts; multiple orthogonal methods\",\n      \"pmids\": [\"29367404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay (MST1 phosphorylation of eIF4E); cap-binding assay; polysome profiling; RNA immunoprecipitation\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay and polysome profiling, cap-binding measured directly; single lab\",\n      \"pmids\": [\"28487214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro reconstituted eIF4F-IRES binding assays; helicase unwinding assays; PV replicon assays; purified viral RNA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — fully reconstituted in vitro system measuring IRES binding affinity and helicase activity; multiple mechanistic readouts in single study\",\n      \"pmids\": [\"28827335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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).\",\n      \"method\": \"Nuclear RNA immunoprecipitation; Co-IP of eIF4E with CPSF components; cleavage assays; knockdown/overexpression studies; multiple validation strategies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNA-IP, functional cleavage assays, knockdown), identifies direct physical interaction and functional consequence; single rigorous study\",\n      \"pmids\": [\"31042468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of Rbm38-eIF4E; RNA immunoprecipitation; peptide competition assay; molecular simulation; mutagenesis (Ser-6 substitution); p53 translation and xenograft assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — binding interface identified by Co-IP and molecular simulation with mutagenesis validation; functional translation rescue; multiple orthogonal methods\",\n      \"pmids\": [\"30591552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-eIF4E knock-in mouse melanoma models; polysome profiling; NGFR translational control assays; immune profiling; anti-PD-1 combination therapy experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic phospho-eIF4E ablation in vivo, specific downstream target (NGFR) identified translationally, immune microenvironment readout, in vivo treatment experiments\",\n      \"pmids\": [\"33690225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"EIF4E heterozygous knockin (S209A) HCT116 cells; spheroid and mouse xenograft growth assays; polysome profiling; CRC organoid growth; Apc mouse polyposis model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise genetic knock-in (S209A), multiple in vitro and in vivo cancer models, translational profiling; multiple orthogonal methods\",\n      \"pmids\": [\"33135632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-type-specific 4E-BP1/4E-BP2 conditional knockout mice; forced swim test; electrophysiology; behavioral pharmacology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockouts, electrophysiological and behavioral readouts, multiple 4E-BP isoforms and cell types examined; rigorous study in Nature\",\n      \"pmids\": [\"33328636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry; Co-IP; genetic knockdown/knockout; ALDH1B1 activity assay; ferroptosis assays in vitro and in vivo; 4EGI-1 and 4E1RCat pharmacological tools\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry-identified interaction, genetic and pharmacological separation of translation-dependent and -independent functions, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"36274088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"eIF4G knockdown; mTOR inhibition (rapamycin); 4E-BP knockdown; eIF4E phosphorylation assays\",\n      \"journal\": \"Translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic disruption of eIF4G-eIF4E interaction with defined phosphorylation readout; single lab, two orthogonal approaches\",\n      \"pmids\": [\"26824022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Ribosome profiling under constitutively active 4E-BP conditions; eIF3d cap-binding pocket mutagenesis; mRNA-eIF3d association assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ribosome profiling with constitutively active 4E-BP genetic tool; eIF3d cap-binding mutant; mechanistic alternative pathway established; multiple orthogonal methods\",\n      \"pmids\": [\"39107322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclear RNA immunoprecipitation; mRNA export assays; polysome analyses; mutational studies separating export vs. translation; RNA-seq in cell lines and AML patient specimens\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (nuclear RIP, export assays, polysome profiling, mutational dissection), validated in patient specimens; single lab but comprehensive mechanistic study\",\n      \"pmids\": [\"36843541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RIP); PRMT5 knockdown; eIF4E overexpression rescue; cell cycle analysis; Western blotting for cap-dependent translation targets\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP assay and epistasis rescue experiment; single lab, limited mechanistic detail on how PRMT5 facilitates eIF4E-mRNA interaction\",\n      \"pmids\": [\"25234597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays; site-directed mutagenesis of Ded1 NTD; PIC assembly assay; polysome analysis; cell growth assays in yeast\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of PIC assembly, site-directed mutagenesis separating Ded1-eIF4A vs. Ded1-eIF4E binding, multiple functional readouts; rigorous study\",\n      \"pmids\": [\"32469309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of PATL2-EIF4E-CPEB1; Patl2 knockout mouse; phosphoproteomics; S279D knock-in mouse; proteasome inhibitor treatment; mRNA quantification in oocytes\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies complex, two genetic mouse models (KO and knock-in), multiple readouts; single lab\",\n      \"pmids\": [\"37218508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Cap-binding assays; polysome profiling; 4E-BP1 phosphorylation analysis; 4E-BP1/2 siRNA knockdown; vemurafenib treatment in BRAF(V600E) melanoma cells\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cap-binding and polysome profiling directly measure eIF4E activity; 4E-BP epistasis established; single lab\",\n      \"pmids\": [\"25615552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay for viral mRNA-eIF4E interaction; molecular docking and molecular dynamics simulation; antiviral assays; pathway inhibition experiments\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP assay for interaction and computational docking; limited biochemical validation of emetine-eIF4E direct binding; single lab, single method for direct binding claim\",\n      \"pmids\": [\"33711336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Covalent docking; cocrystal structure determination; in vitro binding assays; cellular activity assays\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cocrystal structures with functional validation, covalent inhibitor with cellular activity, identifies specific lysine residue; rigorous structural and chemical biology study\",\n      \"pmids\": [\"32105459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Genomic library cloning; primer extension; S1 mapping; ribonuclease protection; RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization with multiple mapping methods; established gene structure and differential expression\",\n      \"pmids\": [\"9468520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; cap-binding assay; yeast complementation assay; in vitro binding assays\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple binding assays (Co-IP, cap binding, yeast complementation) across three family members; clearly distinguishes differential protein-protein interactions; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15153109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF4E is the rate-limiting mRNA 5' m7G cap-binding protein that nucleates the eIF4F complex (with eIF4G and eIF4A) to recruit ribosomes to mRNAs; its activity is regulated by competitive binding of 4E-BPs (controlled by mTOR-dependent phosphorylation), by phosphorylation at Ser209 by MNK1/2 kinases (downstream of ERK/p38 MAPK) which modulates selective mRNA translation rather than global rates, and by sumoylation; in the nucleus, eIF4E promotes export of specific mRNAs, stimulates 3'-end cleavage/polyadenylation, and reprograms alternative splicing by upregulating splice factors; in the cytoplasm, eIF4E localizes to P bodies via eIF4E-T and represses translation of specific mRNAs in developmental contexts; phospho-eIF4E selectively drives translation of mRNAs governing metastasis (Snail, Mmp-3), oncogenesis (Myc, ATF4), neuropsychiatric responses, and pain plasticity, while a noncanonical mitochondrial function of EIF4E represses ALDH1B1 to promote ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #7]. 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 [#1, #8, #11, #21]. 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 [#6, #12, #17, #18, #20]. Sumoylation of eIF4E promotes eIF4F assembly and its pro-proliferative, anti-apoptotic output [#5]. 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 [#4, #15, #23]. 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 [#3, #9, #26]. A noncanonical, translation-independent mitochondrial pool of eIF4E binds and represses ALDH1B1 to promote ferroptosis [#20]. The cap-binding pocket is pharmacologically tractable, with a covalent inhibitor targeting Lys162 demonstrating cellular activity [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical kinase-pathway and 4E-BP binding analyses\",\n      \"pmids\": [\"10216943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the functional consequence of Ser209 phosphorylation on cap affinity\", \"Did not identify mRNA targets selectively controlled\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected eIF4E to mTOR-controlled cell growth, showing eIF4E and 4E-BP1 set cell size downstream of mTOR independently of S6K1.\",\n      \"evidence\": \"Rapamycin-resistant mTOR rescue, dominant-active 4E-BP1, and eIF4E overexpression with cell-size readouts\",\n      \"pmids\": [\"12080086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking eIF4E activity to size at the mRNA level unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Structural and biophysical binding analysis\",\n      \"pmids\": [\"12423333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single analysis paper revising prior model\", \"Functional output of reduced affinity not directly tested in cells\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a cytoplasmic repressive localization for eIF4E, showing eIF4E-T recruits eIF4E into P bodies alongside decay/repression machinery.\",\n      \"evidence\": \"FRET, fluorescence microscopy, and RNAi epistasis in cells\",\n      \"pmids\": [\"15840819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mRNA targets repressed in P bodies not identified here\", \"Signals controlling P-body partitioning unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated competitive eIF4G-mimicry as a repression mechanism, with Maskin gating cyclin B1 translation under CDK1/calcineurin control during the cell cycle.\",\n      \"evidence\": \"In vitro binding, kinase/phosphatase manipulation, and Xenopus cell-cycle translation assays\",\n      \"pmids\": [\"17086181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the motif-mimicry mechanism to mammalian repressors not addressed here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Separated eIF4E's nuclear mRNA-export activity from translation, showing export-competent W73A eIF4E rescues survival via NBS1-Akt and is antagonized by PML.\",\n      \"evidence\": \"Domain-separation mutant, survival rescue, NBS1 export assays, PML epistasis\",\n      \"pmids\": [\"18391071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of export-dependent target mRNAs not catalogued\", \"Mechanism of nuclear export selectivity unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified sumoylation as a PTM that promotes active eIF4F assembly and is required for eIF4E's oncogenic, anti-apoptotic translational output.\",\n      \"evidence\": \"SUMO1 conjugation, eIF4F assembly, and translation/apoptosis assays with sumoylation-deficient mutant\",\n      \"pmids\": [\"20224576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"SUMO acceptor site interplay with phosphorylation not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Clarified crosstalk between the two regulatory arms, showing hypophosphorylated 4E-BP restrains eIF4E phosphorylation by sequestering it from the eIF4G-MNK subcomplex.\",\n      \"evidence\": \"eIF4G/4E-BP knockdown and mTOR inhibition with phosphorylation readouts\",\n      \"pmids\": [\"26824022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative contribution of this route in vivo unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Explained the paradoxical rapamycin-induced rise in eIF4E phosphorylation through Mnk2a activation at a novel Ser437 site.\",\n      \"evidence\": \"Rapamycin treatment, isoform-specific knockdown, and Ser437 mutagenesis\",\n      \"pmids\": [\"23831578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Upstream regulator of Mnk2a Ser437 not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-eIF4E knock-in mouse, polysome profiling, and metastasis assays\",\n      \"pmids\": [\"24909168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full phospho-eIF4E translatome not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended eIF4E-T-dependent repression to development, showing eIF4E1/4E-T/P-body granules sequester proneurogenic mRNAs to maintain neural precursors.\",\n      \"evidence\": \"Reciprocal Co-IP, RIP-seq, RNAi, and neurogenesis assays in mouse cortex\",\n      \"pmids\": [\"25456498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for granule release during differentiation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated PRMT5 as required for eIF4E engagement of specific oncogenic 5'-UTRs (HIF-1\\u03b1, c-Myc, cyclin D1).\",\n      \"evidence\": \"RIP, PRMT5 knockdown, and eIF4E overexpression rescue\",\n      \"pmids\": [\"25234597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular basis of how PRMT5 facilitates eIF4E-mRNA binding unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Haploinsufficient mouse, ribosome profiling, and in vivo tumor models\",\n      \"pmids\": [\"26095252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis-element defining the dose-sensitive 5'-UTR signature not fully mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a mechanism for phospho-eIF4E-driven migration: Ser209 phosphorylation releases CYFIP1 from eIF4E, relieving FMRP repression of metastasis mRNAs like vimentin.\",\n      \"evidence\": \"Mnk1/2 knockout, Mnk inhibitor, eIF4E-CYFIP1 Co-IP, and migration assays\",\n      \"pmids\": [\"25588502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct structural basis of CYFIP1 release not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked eIF4E activity to targeted therapy response, showing BRAF inhibition acts through 4E-BP1-mediated eIF4E sequestration and that increasing eIF4E confers vemurafenib resistance.\",\n      \"evidence\": \"Cap-binding, polysome profiling, and 4E-BP knockdown in BRAF(V600E) melanoma\",\n      \"pmids\": [\"25615552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Specific resistance-driving translated mRNAs not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified MST1 as a non-MNK eIF4E kinase whose phosphorylation weakens cap binding while shifting polysome association toward lncRNAs.\",\n      \"evidence\": \"In vitro kinase, cap-binding, and polysome/RIP assays\",\n      \"pmids\": [\"28487214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological context of MST1-eIF4E signaling undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved eIF4E's role in cap-independent viral translation, showing it enhances eIF4F-IRES binding and eIF4A unwinding on picornavirus IRESes.\",\n      \"evidence\": \"Reconstituted eIF4F-IRES binding and helicase assays with replicon validation\",\n      \"pmids\": [\"28827335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution in infected cells not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-eIF4E knock-in mouse, translational profiling, behavior, and electrophysiology\",\n      \"pmids\": [\"29367404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of behavioral phenotype not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a repressor competing at eIF4E's mRNA interface, with Rbm38 blocking eIF4E-p53 mRNA binding and a disrupting peptide (Pep8) restoring p53 translation.\",\n      \"evidence\": \"Co-IP, RIP, peptide competition, molecular simulation, mutagenesis, and xenograft assays\",\n      \"pmids\": [\"30591552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of Rbm38-style mRNA-selective repression to other transcripts unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Nuclear RIP, Co-IP with CPSF components, cleavage assays, and knockdown/overexpression\",\n      \"pmids\": [\"31042468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of target RNA selectivity for eIF4E-stimulated cleavage unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"S209A knock-in HCT116, organoid/xenograft and Apc polyposis models, polysome profiling\",\n      \"pmids\": [\"33135632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism conferring 5'-UTR selectivity for MYC/ATF4 not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-eIF4E knock-in melanoma models, polysome profiling, immune profiling, anti-PD-1 combination\",\n      \"pmids\": [\"33690225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking NGFR translation to microenvironment remodeling incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed 4E-BPs as the obligate effectors of rapid antidepressants, showing cell-type-specific 4E-BP1/2 requirements for ketamine-induced plasticity and behavior.\",\n      \"evidence\": \"Cell-type-specific conditional 4E-BP knockouts, electrophysiology, and behavioral pharmacology\",\n      \"pmids\": [\"33328636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mRNAs derepressed by 4E-BP loss to mediate antidepressant action not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an eIF4E-independent escape route, showing a subset of mRNAs switches to eIF3d cap-binding when eIF4E1 is sequestered by 4E-BP.\",\n      \"evidence\": \"Ribosome profiling under constitutive 4E-BP and eIF3d cap-pocket mutagenesis\",\n      \"pmids\": [\"39107322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting mRNAs for the eIF3d pathway not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Distinguished separable Ded1 helicase contacts for eIF4A and eIF4E, with the Ded1-eIF4E contact specifically enabling translation of structured 5'-UTR mRNAs.\",\n      \"evidence\": \"In vitro PIC assembly, Ded1 NTD mutagenesis, and polysome/growth assays in yeast\",\n      \"pmids\": [\"32469309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation and role of a Ded1-equivalent eIF4E contact in mammals not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a druggable anchor in the cap pocket, identifying Lys162-targeting covalent arylsulfonyl fluorides as the first covalent eIF4E inhibitors with cellular activity.\",\n      \"evidence\": \"Covalent docking, cocrystal structures, binding and cellular activity assays\",\n      \"pmids\": [\"32105459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity across eIF4E family members and in vivo efficacy not established here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proposed eIF4E as a host factor in SARS-CoV-2 translation disrupted by emetine binding the cap pocket.\",\n      \"evidence\": \"ChIP-based viral mRNA-eIF4E interaction and molecular docking\",\n      \"pmids\": [\"33711336\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct emetine-eIF4E binding shown only computationally; biochemical validation lacking\", \"Single method for the interaction claim\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a translation-independent mitochondrial function, with eIF4E binding and repressing ALDH1B1 to limit 4HNE detoxification and promote ferroptosis.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, genetic and pharmacological separation of functions, in vivo ferroptosis assays\",\n      \"pmids\": [\"36274088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How eIF4E partitions to mitochondria and is regulated there is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected nuclear eIF4E to splicing control, showing export-dependent elevation of SF3B1/U2AF1 reprograms alternative splicing in cells and AML patients.\",\n      \"evidence\": \"Nuclear RIP, export assays, mutational dissection, and RNA-seq in cell lines and AML specimens\",\n      \"pmids\": [\"36843541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect splicing roles not fully disentangled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended eIF4E-CPEB-based maternal mRNA control to mammalian oocytes via the PATL2-eIF4E-CPEB1 complex regulated by PATL2 degradation.\",\n      \"evidence\": \"Co-IP, Patl2 knockout and S279D knock-in mice, phosphoproteomics, and oocyte mRNA/protein quantification\",\n      \"pmids\": [\"37218508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct contribution of eIF4E versus CPEB1 to the phenotype not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 15, 23, 24]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 7, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 11, 16, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 15, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 17, 18, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"eIF4F\",\n      \"P body\",\n      \"PATL2-eIF4E-CPEB1 complex\",\n      \"CPSF 3'-end cleavage complex\"\n    ],\n    \"partners\": [\n      \"EIF4G1\",\n      \"EIF4A\",\n      \"EIF4ENIF1\",\n      \"CYFIP1\",\n      \"CPSF3\",\n      \"RBM38\",\n      \"ALDH1B1\",\n      \"CPEB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}