{"gene":"YWHAE","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2016,"finding":"14-3-3ε (YWHAE) binds to the microtubule-binding protein doublecortin, preventing its degradation; 14-3-3ε overexpression disrupts neurite formation by preventing microtubule invasion into primitive neurites, and this can be rescued by doublecortin knockdown; 14-3-3ε deficiency increases neurite formation in vitro and in vivo.","method":"Co-immunoprecipitation, in vitro binding assays, in vivo mouse (14-3-3ε flox) knockout, live imaging of neurite formation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding assay, KO mouse, rescue experiment) in single study with clear phenotypic readout","pmids":["28173130"],"is_preprint":false},{"year":2021,"finding":"The YWHAE-NUTM2 fusion oncoprotein complexes with both BRAF/RAF1 and YAP/TAZ in high-grade endometrial stromal sarcoma (HG-ESS); YWHAE-NUTM2 knockdown inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation; MEK and CDK4/6 inhibitors have synergistic anti-proliferative effects in HG-ESS.","method":"Co-immunoprecipitation, siRNA knockdown, western blotting, pharmacological inhibition assays","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional knockdown with defined molecular pathway and pharmacological validation","pmids":["33947829"],"is_preprint":false},{"year":2020,"finding":"14-3-3ε (YWHAE) promotes protein synthesis in multiple myeloma cells by binding to and inhibiting the TSC1/TSC2 complex, and by directly interacting with and promoting phosphorylation of mTORC1; 14-3-3ε depletion reduces protein synthesis by up to 50% including immunoglobulin light chain secretion.","method":"Co-immunoprecipitation, siRNA knockdown/overexpression, western blotting, protein synthesis assays, KO cell lines","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated by Co-IP, functional consequence shown by KD/KO with multiple orthogonal readouts","pmids":["32187357"],"is_preprint":false},{"year":2023,"finding":"YWHAE/14-3-3ε is crotonylated at lysines K73 and K78 during leucine deprivation; crotonylation releases PPM1B (a phosphatase) from YWHAE, allowing PPM1B to dephosphorylate ULK1 and activate autophagy; decrotonylation of YWHAE is mediated by HDAC7, whose activity is inhibited during leucine deprivation.","method":"Mass spectrometry crotonylome profiling, site-directed mutagenesis (K73R/K78R), molecular dynamics simulation, co-immunoprecipitation, western blotting","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of modification sites combined with mechanistic downstream pathway validation and structural dynamics analysis","pmids":["36628438"],"is_preprint":false},{"year":2018,"finding":"YWHAE directly interacts with Helicobacter pylori CagA protein; this interaction promotes CagA-enhanced NF-κB transactivation; YWHAE overexpression augments NF-κB activation by CagA, while YWHAE knockdown inhibits it.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunolocalization, siRNA knockdown","journal":"FEMS microbiology letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding assays (Y2H, pulldown, Co-IP) with functional NF-κB reporter readout in single lab","pmids":["29106533"],"is_preprint":false},{"year":2016,"finding":"YWHAE (14-3-3ε) acts as a negative regulator of CDC25B and MYC in gastric cancer cells; YWHAE silencing upregulates CDC25B and MYC, leading to increased cell proliferation, invasion, and migration; MYC reciprocally induces CDC25B expression while reducing YWHAE expression.","method":"siRNA silencing, overexpression constructs, cell proliferation/invasion/migration assays, in vivo xenograft, qRT-PCR, western blotting","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — KD/KO with defined molecular pathway targets and multiple cellular phenotype readouts, in vivo validation","pmids":["27863420"],"is_preprint":false},{"year":2024,"finding":"14-3-3ε/YWHAE negatively regulates cardiac sodium channel NaV1.5 expression: YWHAE binds TBX5 mRNA and decreases its stability, thereby reducing TBX5-mediated transcription of SCN5A; YWHAE knockdown in mice increases sodium current density and causes premature ventricular contractions.","method":"RNA immunoprecipitation, western blotting, patch clamp, qRT-PCR, AAV9-mediated in vivo knockdown, ECG recording","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 1-2 — RNA immunoprecipitation identifies YWHAE-TBX5 mRNA interaction, mutagenesis/KD confirms mechanism, in vivo cardiac phenotype validated by electrophysiology","pmids":["38750908"],"is_preprint":false},{"year":2024,"finding":"ANKZF1 interacts with YWHAE (14-3-3ε) to competitively inhibit YWHAE-driven cytoplasmic retention of YAP1, resulting in YAP1 nuclear import and transcriptional activation of pro-lymphangiogenic factors in clear-cell renal cell carcinoma.","method":"Co-immunoprecipitation, mass spectrometry, RNA immunoprecipitation, immunofluorescence, site-specific mutation analyses, RNA sequencing","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and site-specific mutations with defined functional consequence, single lab study","pmids":["38407929"],"is_preprint":false},{"year":2020,"finding":"14-3-3ε (YWHAE) is essential for male fertility and normal sperm function; testis-specific and global knockout of YWHAE in mice causes infertility, low sperm count, abnormal spermatozoa morphology, and reduced sperm motility; YWHAE KO reduces phosphorylation of GSK3 and PP1γ2 in spermatozoa.","method":"Conditional and global knockout mouse models, computer-assisted semen analysis, immunohistochemistry, western blotting for phosphorylation status","journal":"Andrology","confidence":"High","confidence_rationale":"Tier 2 — Clean KO mouse with defined cellular and molecular phenotype, isoform-specific functional validation","pmids":["32657535"],"is_preprint":false},{"year":2021,"finding":"YWHAE interacts with HE4 protein in ovarian cancer cells; YWHAE-HE4 interaction mediates downstream AKT and MAPK signaling pathway activation; YWHAE knockdown reduces invasion, migration, proliferation and increases apoptosis.","method":"Co-immunoprecipitation, western blotting, immunofluorescence, siRNA knockdown, in vivo xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP confirms interaction, KD with pathway-level readouts, single lab","pmids":["34107979"],"is_preprint":false},{"year":2023,"finding":"TRIP13 forms a complex with YWHAE in multiple myeloma cells; a small molecule DCZ5417 disrupts the TRIP13/YWHAE complex and inhibits ERK/MAPK signaling, suppressing MM cell proliferation.","method":"Molecular docking, pull-down, surface plasmon resonance, cellular thermal shift assay, ATPase assay, co-immunoprecipitation, siRNA/pharmacological approaches","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple biophysical and biochemical binding assays confirm complex; functional disruption tied to defined signaling pathway","pmids":["38012658"],"is_preprint":false},{"year":2019,"finding":"YWHAE lncRNA acts as a competing endogenous RNA (ceRNA) sponging miR-323a-3p and miR-532-5p, thereby preventing miRNA-mediated suppression of K-Ras, and upregulating K-Ras/Erk1/2 and PI3K/Akt signaling pathways in HCT116 colorectal cancer cells.","method":"RNA-seq, RT-qPCR, western blotting, dual luciferase reporter assay, overexpression constructs, wound-healing assay, flow cytometry","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — dual luciferase validates direct miRNA-lncRNA interaction, pathway activation confirmed by western blot, single lab","pmids":["31238337"],"is_preprint":false},{"year":2023,"finding":"YWHAE loss-of-function (heterozygous variants and deletions) in humans causes a neurodevelopmental disorder with corpus callosum hypoplasia, delayed myelination, and ventricular dilatation; Ywhae-/- mice recapitulate brain structural defects including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus.","method":"Human genetic cohort (SNVs and CNVs), Ywhae knockout mouse neuroanatomical phenotyping, MRI","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined neuroanatomical phenotype paralleling human cases; multi-cohort human validation","pmids":["36999555"],"is_preprint":false},{"year":2025,"finding":"METTL3-dependent m6A modification of YWHAE mRNA, recognized by the m6A reader IGF2BP2, enhances YWHAE mRNA stability; YWHAE promotes hepatoblastoma cell proliferation and inhibits ferroptosis by mediating SLC7A11 expression; YWHAE knockdown increases lipid ROS and promotes ferroptosis susceptibility.","method":"RNA sequencing, m6A sequencing, RIP, western blotting, in vitro and in vivo functional studies, ROS/peroxide level assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — m6A-RIP confirms modification and reader interaction, KD with defined ferroptosis pathway readout including molecular target (SLC7A11), single lab","pmids":["40074884"],"is_preprint":false},{"year":2023,"finding":"NKD1 protein binds to the YWHAE gene promoter and transcriptionally activates YWHAE expression in colon cancer cells; NKD1-driven YWHAE upregulation promotes glucose uptake in tumor cells.","method":"ChIP assay, dual luciferase reporter assay, RT-qPCR, western blotting, immunofluorescence, siRNA/overexpression in HCT116 and SW620 cells","journal":"Journal of Southern Medical University","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms NKD1 binding to YWHAE promoter, dual luciferase validates transcriptional activation, functional rescue experiment","pmids":["37202194"],"is_preprint":false},{"year":2008,"finding":"YWHAE (14-3-3ε) interacts with DISC1, NUDEL, and LIS1 as part of a neurodevelopmental complex; Ywhae+/- mice show reduced 14-3-3ε protein to 50% of wild-type and display defects in working memory and enhanced anxiety-like behavior.","method":"Genetic association, Ywhae heterozygous knockout mouse, behavioral testing (eight-arm radial maze, elevated plus-maze), protein expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined behavioral phenotype; interaction with DISC1/NUDEL/LIS1 reported but not directly demonstrated in this paper","pmids":["18658164"],"is_preprint":false},{"year":2021,"finding":"14-3-3ε (YWHAE) regulates neuronal migration by binding to NDEL1, an LIS1-interacting protein, positioning YWHAE downstream of LIS1 in the neuronal migration pathway at 17p13.3.","method":"Review of genetic epistasis and molecular interaction data from prior studies; framed within 17p13.3 gene function context","journal":"Brain sciences","confidence":"Low","confidence_rationale":"Tier 3 — review paper summarizing prior interaction data without presenting new primary experimental evidence","pmids":["35053800"],"is_preprint":false}],"current_model":"YWHAE encodes 14-3-3ε, a phosphoserine/phosphothreonine-binding scaffold protein that regulates neuronal migration (via NDEL1/LIS1 interaction and doublecortin stabilization), cell proliferation and autophagy (via TSC1/TSC2-mTORC1 and crotonylation-dependent ULK1 activation), cardiac sodium channel expression (by binding TBX5 mRNA and reducing its stability), sperm function and male fertility (through GSK3/PP1γ2 phosphorylation regulation), and oncogenic signaling when fused to NUTM2 (activating RAF/MEK/MAPK and Hippo/YAP-TAZ pathways to drive cyclin D1 expression and cell proliferation)."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that YWHAE participates in a neurodevelopmental protein complex (with DISC1, NUDEL, LIS1) and that haploinsufficiency produces cognitive and behavioral deficits addressed whether 14-3-3ε has non-redundant roles in brain function.","evidence":"Ywhae heterozygous knockout mice showing 50% protein reduction with working memory and anxiety phenotypes","pmids":["18658164"],"confidence":"Medium","gaps":["Direct demonstration of DISC1/NUDEL binding not shown in this study","Mechanism linking reduced 14-3-3ε to behavioral deficits not resolved","Contribution of individual complex members unclear"]},{"year":2016,"claim":"Identification of doublecortin as a direct 14-3-3ε client revealed a specific mechanism by which YWHAE controls neurite morphogenesis — by preventing doublecortin degradation and thereby regulating microtubule dynamics in developing neurons.","evidence":"Co-IP, in vitro binding, conditional Ywhae knockout mouse, live imaging with doublecortin knockdown rescue","pmids":["28173130"],"confidence":"High","gaps":["Phosphorylation site on doublecortin mediating 14-3-3ε binding not mapped","Whether other 14-3-3 isoforms compensate in vivo unknown"]},{"year":2016,"claim":"Demonstrating that YWHAE negatively regulates CDC25B and MYC in gastric cancer established a tumor-suppressive role for 14-3-3ε in restraining cell cycle progression and invasion.","evidence":"siRNA knockdown/overexpression in gastric cancer cells with proliferation, invasion, and in vivo xenograft assays","pmids":["27863420"],"confidence":"Medium","gaps":["Direct binding between 14-3-3ε and CDC25B/MYC not demonstrated","Whether this regulation is phosphorylation-dependent unknown"]},{"year":2018,"claim":"Discovery that H. pylori CagA hijacks YWHAE to enhance NF-κB transactivation revealed 14-3-3ε as a host factor exploited by a bacterial oncoprotein.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, and NF-κB reporter assays","pmids":["29106533"],"confidence":"Medium","gaps":["Phosphorylation dependence of CagA–14-3-3ε interaction not fully mapped","In vivo relevance to gastric carcinogenesis not tested"]},{"year":2020,"claim":"Showing that 14-3-3ε promotes mTORC1 activity by sequestering the TSC1/TSC2 inhibitory complex defined a direct mechanism by which YWHAE drives protein synthesis in myeloma cells.","evidence":"Co-IP, siRNA/KO, protein synthesis assays including immunoglobulin light chain secretion in multiple myeloma lines","pmids":["32187357"],"confidence":"High","gaps":["Which phospho-sites on TSC2 mediate 14-3-3ε binding not resolved","Whether this mechanism operates in non-malignant contexts unknown"]},{"year":2020,"claim":"Demonstrating that testis-specific and global Ywhae knockout causes male infertility with abnormal spermatozoa morphology and motility established 14-3-3ε as essential for spermatogenesis, acting through GSK3 and PP1γ2 phosphorylation.","evidence":"Conditional and global knockout mouse models with CASA, immunohistochemistry, and phospho-protein analysis","pmids":["32657535"],"confidence":"High","gaps":["Direct substrates mediating 14-3-3ε effects on sperm capacitation uncharacterized","Whether other 14-3-3 isoforms partially compensate in testis unclear"]},{"year":2021,"claim":"Characterization of the YWHAE-NUTM2 fusion oncoprotein as a scaffold that co-recruits BRAF/RAF1 and YAP/TAZ to drive MAPK signaling and cyclin D1 expression explained the oncogenic mechanism of this translocation in high-grade endometrial stromal sarcoma.","evidence":"Reciprocal Co-IP, siRNA knockdown, pharmacological MEK/CDK4/6 inhibition in HG-ESS cell lines","pmids":["33947829"],"confidence":"High","gaps":["Whether NUTM2 fusion alters 14-3-3ε client specificity beyond BRAF/YAP unknown","Structural basis of the fusion oncoprotein not determined"]},{"year":2023,"claim":"Discovery that crotonylation of 14-3-3ε at K73/K78 during leucine deprivation releases PPM1B to activate ULK1-dependent autophagy uncovered a post-translational switch converting YWHAE from an autophagy suppressor to a permissive state.","evidence":"Crotonylome mass spectrometry, K73R/K78R mutagenesis, molecular dynamics, Co-IP showing PPM1B release","pmids":["36628438"],"confidence":"High","gaps":["Writers responsible for 14-3-3ε crotonylation not identified","Whether crotonylation affects other 14-3-3ε client interactions globally unknown"]},{"year":2023,"claim":"Establishing that heterozygous YWHAE loss-of-function variants cause a human neurodevelopmental disorder with corpus callosum hypoplasia and ventricular dilatation, recapitulated in Ywhae-knockout mice, confirmed YWHAE as a Mendelian disease gene.","evidence":"Human genetic cohort with SNVs/CNVs, Ywhae knockout mouse neuroanatomy, MRI","pmids":["36999555"],"confidence":"High","gaps":["Precise neuronal migration defect underlying human phenotype not delineated at cellular level","Genotype-phenotype correlations across variant types incomplete"]},{"year":2024,"claim":"Revealing that 14-3-3ε binds TBX5 mRNA and reduces its stability, thereby limiting NaV1.5 sodium channel transcription, established an unexpected RNA-binding function for a canonical phosphoprotein scaffold and linked it to cardiac arrhythmia.","evidence":"RNA immunoprecipitation, patch clamp electrophysiology, AAV9-mediated in vivo knockdown with ECG","pmids":["38750908"],"confidence":"High","gaps":["RNA-binding domain or motif within 14-3-3ε not mapped","Whether 14-3-3ε regulates other cardiac mRNAs unknown"]},{"year":2024,"claim":"Demonstrating that ANKZF1 competitively displaces YAP1 from YWHAE, promoting YAP1 nuclear import and lymphangiogenesis in renal cell carcinoma, clarified how YWHAE-mediated cytoplasmic retention of YAP1 is modulated in cancer.","evidence":"Co-IP, mass spectrometry, site-specific mutations, immunofluorescence in clear-cell RCC","pmids":["38407929"],"confidence":"Medium","gaps":["Phospho-sites on YAP1 critical for YWHAE retention not mapped in this study","In vivo validation in RCC models limited"]},{"year":null,"claim":"Key unresolved questions include the structural basis for 14-3-3ε's RNA-binding activity, how crotonylation versus phospho-client binding are coordinated globally, and the extent to which 14-3-3ε functions non-redundantly relative to other 14-3-3 isoforms in specific tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of 14-3-3ε bound to RNA","Systematic mapping of isoform-specific versus shared clients not performed","Integration of crotonylation with other PTMs on 14-3-3ε unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3,7,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,5,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,7,9,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,12,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,12,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,5]}],"complexes":["NDEL1/LIS1/DISC1 complex","TSC1/TSC2 complex (client)","YWHAE-NUTM2 fusion oncoprotein complex"],"partners":["NDEL1","LIS1","DISC1","DCX","TSC2","PPM1B","YAP1","BRAF"],"other_free_text":[]},"mechanistic_narrative":"YWHAE encodes the 14-3-3ε scaffold protein, which regulates diverse cellular processes—including neuronal migration, mTORC1-dependent protein synthesis, autophagy, cardiac electrophysiology, and spermatogenesis—by binding phosphorylated client proteins and modulating their activity, localization, or stability. In neurons, 14-3-3ε stabilizes doublecortin to control neurite formation and participates in an NDEL1/LIS1/DISC1 complex essential for cortical development; heterozygous loss-of-function variants in humans cause a neurodevelopmental disorder with corpus callosum hypoplasia and ventricular dilatation [PMID:28173130, PMID:36999555, PMID:18658164]. 14-3-3ε promotes mTORC1 signaling by sequestering the TSC1/TSC2 complex, and its crotonylation at K73/K78 during leucine deprivation releases the phosphatase PPM1B to dephosphorylate ULK1 and activate autophagy [PMID:32187357, PMID:36628438]. Beyond canonical phosphoprotein scaffolding, 14-3-3ε binds TBX5 mRNA to reduce its stability and thereby limits NaV1.5 cardiac sodium channel expression, and it retains YAP1 in the cytoplasm to restrain Hippo pathway transcriptional output [PMID:38750908, PMID:38407929]."},"prefetch_data":{"uniprot":{"accession":"P62258","full_name":"14-3-3 protein epsilon","aliases":[],"length_aa":255,"mass_kda":29.2,"function":"Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (PubMed:21189250). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (PubMed:35343654). Binding generally results in the modulation of the activity of the binding partner (By similarity). Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm (PubMed:12917326). Plays a positive role in the antiviral signaling pathway upstream of TBK1 via interaction with RIGI (PubMed:37555661). Mechanistically, directs RIGI redistribution from the cytosol to mitochondrial associated membranes where it mediates MAVS-dependent innate immune signaling during viral infection (PubMed:22607805). Plays a role in proliferation inhibition and cell cycle arrest by exporting HNRNPC from the nucleus to the cytoplasm to be degraded by ubiquitination (PubMed:37599448)","subcellular_location":"Nucleus; Cytoplasm; Melanosome","url":"https://www.uniprot.org/uniprotkb/P62258/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YWHAE","classification":"Not Classified","n_dependent_lines":463,"n_total_lines":1165,"dependency_fraction":0.39742489270386266},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108953","cell_line_id":"CID000463","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"centrosome","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"YWHAB","stoichiometry":10.0},{"gene":"YWHAH","stoichiometry":10.0},{"gene":"YWHAZ","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":4.0},{"gene":"YWHAQ","stoichiometry":4.0},{"gene":"ACTR2","stoichiometry":0.2},{"gene":"AKT1S1","stoichiometry":0.2},{"gene":"APPL1","stoichiometry":0.2},{"gene":"ARHGEF7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000463","total_profiled":1310},"omim":[{"mim_id":"617998","title":"GRB2-ASSOCIATED REGULATOR OF MAPK1, SUBTYPE 1; GAREM1","url":"https://www.omim.org/entry/617998"},{"mim_id":"617289","title":"FAMILY WITH SEQUENCE SIMILARITY 53, MEMBER B; FAM53B","url":"https://www.omim.org/entry/617289"},{"mim_id":"613215","title":"CHROMOSOME 17p13.3, CENTROMERIC, DUPLICATION SYNDROME","url":"https://www.omim.org/entry/613215"},{"mim_id":"612576","title":"CHROMOSOME 17p13.3, TELOMERIC, DUPLICATION SYNDROME","url":"https://www.omim.org/entry/612576"},{"mim_id":"610679","title":"CYCLIN-DEPENDENT KINASE 14; CDK14","url":"https://www.omim.org/entry/610679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YWHAE"},"hgnc":{"alias_symbol":["FLJ45465"],"prev_symbol":[]},"alphafold":{"accession":"P62258","domains":[{"cath_id":"1.20.190.20","chopping":"1-111","consensus_level":"medium","plddt":96.1653,"start":1,"end":111},{"cath_id":"1.20.190.20","chopping":"116-255","consensus_level":"medium","plddt":90.1248,"start":116,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62258","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62258-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62258-F1-predicted_aligned_error_v6.png","plddt_mean":92.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YWHAE","jax_strain_url":"https://www.jax.org/strain/search?query=YWHAE"},"sequence":{"accession":"P62258","fasta_url":"https://rest.uniprot.org/uniprotkb/P62258.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62258/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62258"}},"corpus_meta":[{"pmid":"22456610","id":"PMC_22456610","title":"The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor.","date":"2012","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22456610","citation_count":204,"is_preprint":false},{"pmid":"26945340","id":"PMC_26945340","title":"Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney.","date":"2016","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26945340","citation_count":164,"is_preprint":false},{"pmid":"22982899","id":"PMC_22982899","title":"Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement.","date":"2012","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22982899","citation_count":133,"is_preprint":false},{"pmid":"19584063","id":"PMC_19584063","title":"Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment.","date":"2009","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19584063","citation_count":99,"is_preprint":false},{"pmid":"18658164","id":"PMC_18658164","title":"Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18658164","citation_count":87,"is_preprint":false},{"pmid":"32034283","id":"PMC_32034283","title":"NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations.","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/32034283","citation_count":64,"is_preprint":false},{"pmid":"23599159","id":"PMC_23599159","title":"YWHAE rearrangement identified by FISH and RT-PCR in endometrial stromal sarcomas: genetic and pathological correlations.","date":"2013","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/23599159","citation_count":56,"is_preprint":false},{"pmid":"27000436","id":"PMC_27000436","title":"Mutually exclusive BCOR internal tandem duplications and YWHAE-NUTM2 fusions in clear cell sarcoma of kidney: not the full story.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27000436","citation_count":54,"is_preprint":false},{"pmid":"24186140","id":"PMC_24186140","title":"Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement.","date":"2013","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/24186140","citation_count":52,"is_preprint":false},{"pmid":"32372022","id":"PMC_32372022","title":"Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study.","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/32372022","citation_count":51,"is_preprint":false},{"pmid":"27863420","id":"PMC_27863420","title":"YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis 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Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε). 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14-3-3ε overexpression disrupts neurite formation by preventing microtubule invasion into primitive neurites, and this can be rescued by doublecortin knockdown; 14-3-3ε deficiency increases neurite formation in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, in vivo mouse (14-3-3ε flox) knockout, live imaging of neurite formation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assay, KO mouse, rescue experiment) in single study with clear phenotypic readout\",\n      \"pmids\": [\"28173130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The YWHAE-NUTM2 fusion oncoprotein complexes with both BRAF/RAF1 and YAP/TAZ in high-grade endometrial stromal sarcoma (HG-ESS); YWHAE-NUTM2 knockdown inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation; MEK and CDK4/6 inhibitors have synergistic anti-proliferative effects in HG-ESS.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blotting, pharmacological inhibition assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional knockdown with defined molecular pathway and pharmacological validation\",\n      \"pmids\": [\"33947829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"14-3-3ε (YWHAE) promotes protein synthesis in multiple myeloma cells by binding to and inhibiting the TSC1/TSC2 complex, and by directly interacting with and promoting phosphorylation of mTORC1; 14-3-3ε depletion reduces protein synthesis by up to 50% including immunoglobulin light chain secretion.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown/overexpression, western blotting, protein synthesis assays, KO cell lines\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by Co-IP, functional consequence shown by KD/KO with multiple orthogonal readouts\",\n      \"pmids\": [\"32187357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YWHAE/14-3-3ε is crotonylated at lysines K73 and K78 during leucine deprivation; crotonylation releases PPM1B (a phosphatase) from YWHAE, allowing PPM1B to dephosphorylate ULK1 and activate autophagy; decrotonylation of YWHAE is mediated by HDAC7, whose activity is inhibited during leucine deprivation.\",\n      \"method\": \"Mass spectrometry crotonylome profiling, site-directed mutagenesis (K73R/K78R), molecular dynamics simulation, co-immunoprecipitation, western blotting\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of modification sites combined with mechanistic downstream pathway validation and structural dynamics analysis\",\n      \"pmids\": [\"36628438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YWHAE directly interacts with Helicobacter pylori CagA protein; this interaction promotes CagA-enhanced NF-κB transactivation; YWHAE overexpression augments NF-κB activation by CagA, while YWHAE knockdown inhibits it.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunolocalization, siRNA knockdown\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays (Y2H, pulldown, Co-IP) with functional NF-κB reporter readout in single lab\",\n      \"pmids\": [\"29106533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YWHAE (14-3-3ε) acts as a negative regulator of CDC25B and MYC in gastric cancer cells; YWHAE silencing upregulates CDC25B and MYC, leading to increased cell proliferation, invasion, and migration; MYC reciprocally induces CDC25B expression while reducing YWHAE expression.\",\n      \"method\": \"siRNA silencing, overexpression constructs, cell proliferation/invasion/migration assays, in vivo xenograft, qRT-PCR, western blotting\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/KO with defined molecular pathway targets and multiple cellular phenotype readouts, in vivo validation\",\n      \"pmids\": [\"27863420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"14-3-3ε/YWHAE negatively regulates cardiac sodium channel NaV1.5 expression: YWHAE binds TBX5 mRNA and decreases its stability, thereby reducing TBX5-mediated transcription of SCN5A; YWHAE knockdown in mice increases sodium current density and causes premature ventricular contractions.\",\n      \"method\": \"RNA immunoprecipitation, western blotting, patch clamp, qRT-PCR, AAV9-mediated in vivo knockdown, ECG recording\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNA immunoprecipitation identifies YWHAE-TBX5 mRNA interaction, mutagenesis/KD confirms mechanism, in vivo cardiac phenotype validated by electrophysiology\",\n      \"pmids\": [\"38750908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANKZF1 interacts with YWHAE (14-3-3ε) to competitively inhibit YWHAE-driven cytoplasmic retention of YAP1, resulting in YAP1 nuclear import and transcriptional activation of pro-lymphangiogenic factors in clear-cell renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNA immunoprecipitation, immunofluorescence, site-specific mutation analyses, RNA sequencing\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and site-specific mutations with defined functional consequence, single lab study\",\n      \"pmids\": [\"38407929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"14-3-3ε (YWHAE) is essential for male fertility and normal sperm function; testis-specific and global knockout of YWHAE in mice causes infertility, low sperm count, abnormal spermatozoa morphology, and reduced sperm motility; YWHAE KO reduces phosphorylation of GSK3 and PP1γ2 in spermatozoa.\",\n      \"method\": \"Conditional and global knockout mouse models, computer-assisted semen analysis, immunohistochemistry, western blotting for phosphorylation status\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Clean KO mouse with defined cellular and molecular phenotype, isoform-specific functional validation\",\n      \"pmids\": [\"32657535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YWHAE interacts with HE4 protein in ovarian cancer cells; YWHAE-HE4 interaction mediates downstream AKT and MAPK signaling pathway activation; YWHAE knockdown reduces invasion, migration, proliferation and increases apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, immunofluorescence, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP confirms interaction, KD with pathway-level readouts, single lab\",\n      \"pmids\": [\"34107979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIP13 forms a complex with YWHAE in multiple myeloma cells; a small molecule DCZ5417 disrupts the TRIP13/YWHAE complex and inhibits ERK/MAPK signaling, suppressing MM cell proliferation.\",\n      \"method\": \"Molecular docking, pull-down, surface plasmon resonance, cellular thermal shift assay, ATPase assay, co-immunoprecipitation, siRNA/pharmacological approaches\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple biophysical and biochemical binding assays confirm complex; functional disruption tied to defined signaling pathway\",\n      \"pmids\": [\"38012658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YWHAE lncRNA acts as a competing endogenous RNA (ceRNA) sponging miR-323a-3p and miR-532-5p, thereby preventing miRNA-mediated suppression of K-Ras, and upregulating K-Ras/Erk1/2 and PI3K/Akt signaling pathways in HCT116 colorectal cancer cells.\",\n      \"method\": \"RNA-seq, RT-qPCR, western blotting, dual luciferase reporter assay, overexpression constructs, wound-healing assay, flow cytometry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual luciferase validates direct miRNA-lncRNA interaction, pathway activation confirmed by western blot, single lab\",\n      \"pmids\": [\"31238337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YWHAE loss-of-function (heterozygous variants and deletions) in humans causes a neurodevelopmental disorder with corpus callosum hypoplasia, delayed myelination, and ventricular dilatation; Ywhae-/- mice recapitulate brain structural defects including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus.\",\n      \"method\": \"Human genetic cohort (SNVs and CNVs), Ywhae knockout mouse neuroanatomical phenotyping, MRI\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined neuroanatomical phenotype paralleling human cases; multi-cohort human validation\",\n      \"pmids\": [\"36999555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-dependent m6A modification of YWHAE mRNA, recognized by the m6A reader IGF2BP2, enhances YWHAE mRNA stability; YWHAE promotes hepatoblastoma cell proliferation and inhibits ferroptosis by mediating SLC7A11 expression; YWHAE knockdown increases lipid ROS and promotes ferroptosis susceptibility.\",\n      \"method\": \"RNA sequencing, m6A sequencing, RIP, western blotting, in vitro and in vivo functional studies, ROS/peroxide level assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A-RIP confirms modification and reader interaction, KD with defined ferroptosis pathway readout including molecular target (SLC7A11), single lab\",\n      \"pmids\": [\"40074884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NKD1 protein binds to the YWHAE gene promoter and transcriptionally activates YWHAE expression in colon cancer cells; NKD1-driven YWHAE upregulation promotes glucose uptake in tumor cells.\",\n      \"method\": \"ChIP assay, dual luciferase reporter assay, RT-qPCR, western blotting, immunofluorescence, siRNA/overexpression in HCT116 and SW620 cells\",\n      \"journal\": \"Journal of Southern Medical University\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms NKD1 binding to YWHAE promoter, dual luciferase validates transcriptional activation, functional rescue experiment\",\n      \"pmids\": [\"37202194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"YWHAE (14-3-3ε) interacts with DISC1, NUDEL, and LIS1 as part of a neurodevelopmental complex; Ywhae+/- mice show reduced 14-3-3ε protein to 50% of wild-type and display defects in working memory and enhanced anxiety-like behavior.\",\n      \"method\": \"Genetic association, Ywhae heterozygous knockout mouse, behavioral testing (eight-arm radial maze, elevated plus-maze), protein expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined behavioral phenotype; interaction with DISC1/NUDEL/LIS1 reported but not directly demonstrated in this paper\",\n      \"pmids\": [\"18658164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"14-3-3ε (YWHAE) regulates neuronal migration by binding to NDEL1, an LIS1-interacting protein, positioning YWHAE downstream of LIS1 in the neuronal migration pathway at 17p13.3.\",\n      \"method\": \"Review of genetic epistasis and molecular interaction data from prior studies; framed within 17p13.3 gene function context\",\n      \"journal\": \"Brain sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review paper summarizing prior interaction data without presenting new primary experimental evidence\",\n      \"pmids\": [\"35053800\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YWHAE encodes 14-3-3ε, a phosphoserine/phosphothreonine-binding scaffold protein that regulates neuronal migration (via NDEL1/LIS1 interaction and doublecortin stabilization), cell proliferation and autophagy (via TSC1/TSC2-mTORC1 and crotonylation-dependent ULK1 activation), cardiac sodium channel expression (by binding TBX5 mRNA and reducing its stability), sperm function and male fertility (through GSK3/PP1γ2 phosphorylation regulation), and oncogenic signaling when fused to NUTM2 (activating RAF/MEK/MAPK and Hippo/YAP-TAZ pathways to drive cyclin D1 expression and cell proliferation).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YWHAE encodes the 14-3-3ε scaffold protein, which regulates diverse cellular processes—including neuronal migration, mTORC1-dependent protein synthesis, autophagy, cardiac electrophysiology, and spermatogenesis—by binding phosphorylated client proteins and modulating their activity, localization, or stability. In neurons, 14-3-3ε stabilizes doublecortin to control neurite formation and participates in an NDEL1/LIS1/DISC1 complex essential for cortical development; heterozygous loss-of-function variants in humans cause a neurodevelopmental disorder with corpus callosum hypoplasia and ventricular dilatation [PMID:28173130, PMID:36999555, PMID:18658164]. 14-3-3ε promotes mTORC1 signaling by sequestering the TSC1/TSC2 complex, and its crotonylation at K73/K78 during leucine deprivation releases the phosphatase PPM1B to dephosphorylate ULK1 and activate autophagy [PMID:32187357, PMID:36628438]. Beyond canonical phosphoprotein scaffolding, 14-3-3ε binds TBX5 mRNA to reduce its stability and thereby limits NaV1.5 cardiac sodium channel expression, and it retains YAP1 in the cytoplasm to restrain Hippo pathway transcriptional output [PMID:38750908, PMID:38407929].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that YWHAE participates in a neurodevelopmental protein complex (with DISC1, NUDEL, LIS1) and that haploinsufficiency produces cognitive and behavioral deficits addressed whether 14-3-3ε has non-redundant roles in brain function.\",\n      \"evidence\": \"Ywhae heterozygous knockout mice showing 50% protein reduction with working memory and anxiety phenotypes\",\n      \"pmids\": [\"18658164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of DISC1/NUDEL binding not shown in this study\", \"Mechanism linking reduced 14-3-3ε to behavioral deficits not resolved\", \"Contribution of individual complex members unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of doublecortin as a direct 14-3-3ε client revealed a specific mechanism by which YWHAE controls neurite morphogenesis — by preventing doublecortin degradation and thereby regulating microtubule dynamics in developing neurons.\",\n      \"evidence\": \"Co-IP, in vitro binding, conditional Ywhae knockout mouse, live imaging with doublecortin knockdown rescue\",\n      \"pmids\": [\"28173130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site on doublecortin mediating 14-3-3ε binding not mapped\", \"Whether other 14-3-3 isoforms compensate in vivo unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that YWHAE negatively regulates CDC25B and MYC in gastric cancer established a tumor-suppressive role for 14-3-3ε in restraining cell cycle progression and invasion.\",\n      \"evidence\": \"siRNA knockdown/overexpression in gastric cancer cells with proliferation, invasion, and in vivo xenograft assays\",\n      \"pmids\": [\"27863420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between 14-3-3ε and CDC25B/MYC not demonstrated\", \"Whether this regulation is phosphorylation-dependent unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that H. pylori CagA hijacks YWHAE to enhance NF-κB transactivation revealed 14-3-3ε as a host factor exploited by a bacterial oncoprotein.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, and NF-κB reporter assays\",\n      \"pmids\": [\"29106533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation dependence of CagA–14-3-3ε interaction not fully mapped\", \"In vivo relevance to gastric carcinogenesis not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that 14-3-3ε promotes mTORC1 activity by sequestering the TSC1/TSC2 inhibitory complex defined a direct mechanism by which YWHAE drives protein synthesis in myeloma cells.\",\n      \"evidence\": \"Co-IP, siRNA/KO, protein synthesis assays including immunoglobulin light chain secretion in multiple myeloma lines\",\n      \"pmids\": [\"32187357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which phospho-sites on TSC2 mediate 14-3-3ε binding not resolved\", \"Whether this mechanism operates in non-malignant contexts unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that testis-specific and global Ywhae knockout causes male infertility with abnormal spermatozoa morphology and motility established 14-3-3ε as essential for spermatogenesis, acting through GSK3 and PP1γ2 phosphorylation.\",\n      \"evidence\": \"Conditional and global knockout mouse models with CASA, immunohistochemistry, and phospho-protein analysis\",\n      \"pmids\": [\"32657535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates mediating 14-3-3ε effects on sperm capacitation uncharacterized\", \"Whether other 14-3-3 isoforms partially compensate in testis unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterization of the YWHAE-NUTM2 fusion oncoprotein as a scaffold that co-recruits BRAF/RAF1 and YAP/TAZ to drive MAPK signaling and cyclin D1 expression explained the oncogenic mechanism of this translocation in high-grade endometrial stromal sarcoma.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, pharmacological MEK/CDK4/6 inhibition in HG-ESS cell lines\",\n      \"pmids\": [\"33947829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NUTM2 fusion alters 14-3-3ε client specificity beyond BRAF/YAP unknown\", \"Structural basis of the fusion oncoprotein not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that crotonylation of 14-3-3ε at K73/K78 during leucine deprivation releases PPM1B to activate ULK1-dependent autophagy uncovered a post-translational switch converting YWHAE from an autophagy suppressor to a permissive state.\",\n      \"evidence\": \"Crotonylome mass spectrometry, K73R/K78R mutagenesis, molecular dynamics, Co-IP showing PPM1B release\",\n      \"pmids\": [\"36628438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Writers responsible for 14-3-3ε crotonylation not identified\", \"Whether crotonylation affects other 14-3-3ε client interactions globally unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that heterozygous YWHAE loss-of-function variants cause a human neurodevelopmental disorder with corpus callosum hypoplasia and ventricular dilatation, recapitulated in Ywhae-knockout mice, confirmed YWHAE as a Mendelian disease gene.\",\n      \"evidence\": \"Human genetic cohort with SNVs/CNVs, Ywhae knockout mouse neuroanatomy, MRI\",\n      \"pmids\": [\"36999555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise neuronal migration defect underlying human phenotype not delineated at cellular level\", \"Genotype-phenotype correlations across variant types incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing that 14-3-3ε binds TBX5 mRNA and reduces its stability, thereby limiting NaV1.5 sodium channel transcription, established an unexpected RNA-binding function for a canonical phosphoprotein scaffold and linked it to cardiac arrhythmia.\",\n      \"evidence\": \"RNA immunoprecipitation, patch clamp electrophysiology, AAV9-mediated in vivo knockdown with ECG\",\n      \"pmids\": [\"38750908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding domain or motif within 14-3-3ε not mapped\", \"Whether 14-3-3ε regulates other cardiac mRNAs unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that ANKZF1 competitively displaces YAP1 from YWHAE, promoting YAP1 nuclear import and lymphangiogenesis in renal cell carcinoma, clarified how YWHAE-mediated cytoplasmic retention of YAP1 is modulated in cancer.\",\n      \"evidence\": \"Co-IP, mass spectrometry, site-specific mutations, immunofluorescence in clear-cell RCC\",\n      \"pmids\": [\"38407929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phospho-sites on YAP1 critical for YWHAE retention not mapped in this study\", \"In vivo validation in RCC models limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for 14-3-3ε's RNA-binding activity, how crotonylation versus phospho-client binding are coordinated globally, and the extent to which 14-3-3ε functions non-redundantly relative to other 14-3-3 isoforms in specific tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of 14-3-3ε bound to RNA\", \"Systematic mapping of isoform-specific versus shared clients not performed\", \"Integration of crotonylation with other PTMs on 14-3-3ε unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 12, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 12, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [\n      \"NDEL1/LIS1/DISC1 complex\",\n      \"TSC1/TSC2 complex (client)\",\n      \"YWHAE-NUTM2 fusion oncoprotein complex\"\n    ],\n    \"partners\": [\n      \"NDEL1\",\n      \"LIS1\",\n      \"DISC1\",\n      \"DCX\",\n      \"TSC2\",\n      \"PPM1B\",\n      \"YAP1\",\n      \"BRAF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}