{"gene":"YWHAE","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"14-3-3ε (YWHAE) binds to the microtubule-binding protein doublecortin (DCX), preventing its degradation. Overexpression of 14-3-3ε disrupts neurite formation by preventing microtubule invasion into primitive neurites, an effect rescuable by DCX knockdown. Conversely, 14-3-3ε deficiency (flox knockout) increases neurite formation.","method":"Co-immunoprecipitation/binding assay, in vitro and in vivo (14-3-3ε flox mice) techniques, neurite formation imaging, rescue by siRNA knockdown","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay, in vivo knockout model, and rescue experiment; multiple orthogonal methods in single study","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. Cyclin D1 knockdown dephosphorylates RB1 and inhibits proliferation. MEK and CDK4/6 inhibitors have synergistic anti-proliferative effects in HG-ESS.","method":"Co-immunoprecipitation (BRAF/RAF1 and YAP/TAZ), siRNA knockdown of YWHAE-NUTM2 and cyclin D1 with proliferation/phosphorylation readouts, pharmacological inhibition","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, knockdown with multiple downstream readouts (phosphorylation, cyclin D1, RB1, proliferation), pharmacological validation; single lab but multiple orthogonal methods","pmids":["33947829"],"is_preprint":false},{"year":2023,"finding":"YWHAE/14-3-3ε undergoes lysine crotonylation at K73 and K78 during leucine deprivation-induced autophagy. Blocking crotonylation (K73R/K78R mutants) attenuates autophagy. Crotonylation of YWHAE releases PPM1B, which then dephosphorylates ULK1 to activate autophagy. Decrotonylation of YWHAE is mediated by HDAC7, whose activity is inhibited by leucine deprivation.","method":"Crotonylome mass spectrometry, site-directed mutagenesis (K73R/K78R), molecular dynamics simulation, biochemical assays for ULK1 phosphorylation and PPM1B interaction","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis, mass spectrometry-based PTM identification, molecular dynamics, functional autophagy readouts; multiple orthogonal methods in single study","pmids":["36628438"],"is_preprint":false},{"year":2020,"finding":"14-3-3ε (YWHAE) promotes translation initiation and protein synthesis in multiple myeloma cells through binding and inhibition of the TSC1/TSC2 complex, and directly interacts with and promotes phosphorylation of mTORC1. 14-3-3ε depletion reduces protein synthesis by ~50% and decreases immunoglobulin light chain secretion; overexpression or addback restores protein synthesis and protein load.","method":"Co-immunoprecipitation (TSC1/TSC2, mTORC1), siRNA knockdown and overexpression with protein synthesis measurement, immunoglobulin secretion assay, knockout with addback","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for TSC1/TSC2 and mTORC1 interactions, KO/OE with quantitative protein synthesis readouts and rescue; multiple orthogonal methods","pmids":["32187357"],"is_preprint":false},{"year":2016,"finding":"YWHAE silencing in gastric cancer cells upregulates CDC25B and MYC expression, leading to increased cell proliferation, invasion, and migration. YWHAE acts as a negative regulator of the cyclin phosphatase CDC25B and the MYC oncogene. Conversely, MYC induces CDC25B and reduces YWHAE expression.","method":"siRNA knockdown of YWHAE, CDC25B, and MYC in gastric cancer cell lines; proliferation, invasion, migration assays; expression analysis in cell lines and tumor samples","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with cellular phenotypic readouts and reciprocal regulation; single lab, no direct binding assay","pmids":["27863420"],"is_preprint":false},{"year":2018,"finding":"YWHAE interacts directly with H. pylori virulence factor CagA. This interaction was identified by yeast two-hybrid screen and validated by GST pull-down, co-immunoprecipitation, and immunolocalization. Overexpression of YWHAE promotes CagA-mediated NF-κB activation; knockdown of YWHAE inhibits NF-κB activation by CagA.","method":"GAL4 yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, immunolocalization, YWHAE overexpression/knockdown with NF-κB reporter assay","journal":"FEMS microbiology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus Co-IP plus functional NF-κB readout with OE/KD; single lab, multiple orthogonal binding methods","pmids":["29106533"],"is_preprint":false},{"year":2024,"finding":"ANKZF1 interacts with YWHAE to competitively inhibit YWHAE-driven cytoplasmic retention of YAP1, leading to nuclear import of YAP1 and transcriptional activation of pro-lymphangiogenic factors in clear-cell renal cell carcinoma.","method":"Co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, mass spectrometry, site-specific mutation analyses, RNA sequencing","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and immunofluorescence to validate ANKZF1-YWHAE interaction and YAP1 localization, supported by mutagenesis; single lab","pmids":["38407929"],"is_preprint":false},{"year":2020,"finding":"14-3-3ε (YWHAE) is essential for male fertility: it is expressed in spermatozoa (unlike 14-3-3η), and testis-specific and global knockout of Ywhae in mice causes infertility with low sperm count, higher sperm abnormalities, and reduced sperm motility. Knockout spermatozoa show reduced phosphorylation of glycogen synthase kinase 3 and PP1γ2.","method":"Conditional knockout (CKO) and global knockout (GKO) mouse models, computer-assisted semen analysis, immunohistochemistry, western blot for GSK3 and PP1γ2 phosphorylation","journal":"Andrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean isoform-specific knockout with defined fertility and sperm motility phenotype, biochemical substrate phosphorylation readout; replicated in CKO and GKO models","pmids":["32657535"],"is_preprint":false},{"year":2023,"finding":"DCZ5417 (a norcantharidin derivative) targets TRIP13 ATPase and disrupts the TRIP13/YWHAE protein complex, thereby inhibiting ERK/MAPK signaling and suppressing multiple myeloma cell proliferation. The anti-myeloma activity depends on TRIP13.","method":"Molecular docking, pull-down assay, surface plasmon resonance binding assay, cellular thermal shift assay, ATPase assay, Co-IP for TRIP13/YWHAE complex, genetic and pharmacological epistasis","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple direct binding methods (pull-down, SPR, CETSA) plus functional complex disruption readout; single lab","pmids":["38012658"],"is_preprint":false},{"year":2024,"finding":"14-3-3ε/YWHAE negatively regulates cardiac NaV1.5 expression by binding to and destabilizing TBX5 mRNA (a transcription factor for SCN5A), thereby decreasing SCN5A mRNA levels and sodium current density. YWHAE knockdown in mice (via AAV9) increases SCN5A mRNA and sodium current and leads to shorter R-R intervals and higher prevalence of premature ventricular contractions.","method":"Western blotting, patch clamping, RT-PCR, RNA immunoprecipitation (14-3-3ε with TBX5 mRNA), AAV9-mediated YWHAE knockdown in mice, electrocardiogram, echocardiography; TBX5 knockdown epistasis","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation identifying mRNA binding, electrophysiology, in vivo AAV knockdown, epistasis with TBX5; multiple orthogonal methods in single study","pmids":["38750908"],"is_preprint":false},{"year":2025,"finding":"N6-methyladenosine (m6A) modification of YWHAE mRNA by METTL3, read by IGF2BP2, enhances YWHAE mRNA stability and promotes its expression in hepatoblastoma. YWHAE knockdown increases lipid ROS and peroxides, enhancing ferroptosis susceptibility, partly through downregulation of SLC7A11.","method":"m6A sequencing, RNA sequencing, m6A-RIP, co-immunoprecipitation, in vitro and in vivo knockdown studies, lipid ROS/peroxide assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP for writer/reader identification, in vitro and in vivo KD with ferroptosis readouts; single lab, multiple methods","pmids":["40074884"],"is_preprint":false},{"year":2023,"finding":"NKD1 protein binds to the YWHAE gene promoter and activates YWHAE transcription in colon cancer cells. NKD1 overexpression increases YWHAE mRNA and protein; NKD1 knockout reduces both. YWHAE overexpression rescues the glucose uptake deficit caused by NKD1 knockout, placing YWHAE downstream of NKD1 in glucose metabolism regulation.","method":"Chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay, RT-qPCR, western blot, immunofluorescence, glucose uptake assay, NKD1 knockout and YWHAE overexpression rescue","journal":"Journal of Southern Medical University","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for direct promoter binding, functional rescue experiment; single lab","pmids":["37202194"],"is_preprint":false},{"year":2025,"finding":"Ywhae (14-3-3ε) knockdown in 3T3-L1 pre-adipocytes enhances Alpl (alkaline phosphatase) expression even without DNA demethylation treatment, identifying YWHAE/Ywhae as a suppressor of osteogenic gene expression in mesenchymal precursors.","method":"siRNA knockdown in 3T3-L1 cells, ALP activity assay, transcriptomic and epigenomic profiling","journal":"Epigenomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown with ALP readout; single lab, limited mechanistic depth","pmids":["40792537"],"is_preprint":false},{"year":2022,"finding":"miR-29b-3p targets the 3'UTR of YWHAE mRNA (validated by dual luciferase assay) and inhibits YWHAE expression, resulting in decreased p-BAD/BAD ratio and increased BAX/BCL-2 ratio in 22Rv1 prostate cancer cells, promoting apoptosis. YWHAE overexpression reverses the anti-proliferative effects of miR-29b-3p.","method":"Dual luciferase reporter assay (miR-29b-3p targeting YWHAE 3'UTR), siRNA/miRNA overexpression, western blot (BAD, BAX, BCL-2, caspase-3), proliferation/apoptosis assays, in vivo xenograft rescue","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting validated by luciferase, multiple apoptosis markers, in vivo rescue; single lab","pmids":["35928803"],"is_preprint":false},{"year":2021,"finding":"YWHAE interacts with HE4 (WFDC2) in ovarian cancer cells, as demonstrated by co-immunoprecipitation and co-immunofluorescence. YWHAE overexpression enhances invasion, migration, and proliferation while inhibiting apoptosis of ovarian cancer cells through the AKT and MAPK signaling pathways.","method":"Co-immunoprecipitation, western blot, cellular immunofluorescence, YWHAE overexpression/knockdown with invasion/migration/proliferation/apoptosis assays, in vivo experiments","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for HE4 interaction, functional assays with OE/KD; single lab, multiple phenotypic readouts","pmids":["34107979"],"is_preprint":false},{"year":2024,"finding":"miR-873-5p directly targets YWHAE 3'UTR (validated by dual-luciferase assay and RIP), suppressing YWHAE expression and inhibiting NSCLC cell proliferation, migration, invasion, and EMT. YWHAE promotes PI3K/AKT pathway activation; miR-873-5p overexpression inhibits the YWHAE-mediated PI3K/AKT signaling cascade and reverses gefitinib resistance by inducing autophagy.","method":"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), western blot (YWHAE, PI3K, AKT), CCK8, colony formation, Transwell, miR-873-5p overexpression","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase and RIP for direct targeting, pathway western blots, functional rescue; single lab","pmids":["38363382"],"is_preprint":false},{"year":2023,"finding":"Ywhae (14-3-3ε) knockout mice show brain structural defects including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus, paralleling neurodevelopmental brain abnormalities seen in human patients with YWHAE loss-of-function variants.","method":"Ywhae-/- mouse knockout, neuroanatomical studies (histology, brain imaging), clinical phenotyping of 10 human patients with heterozygous YWHAE loss-of-function variants","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mouse knockout with defined neuroanatomical phenotypes replicated in human patients; translational replication across species","pmids":["36999555"],"is_preprint":false},{"year":2025,"finding":"YWHAE is identified as a ferroptosis-associated gene upregulated in ARDS. In an LPS-induced ARDS mouse model, the ferroptosis inhibitor ferrostatin-1 attenuates lung injury and downregulates YWHAE expression, suggesting YWHAE expression is linked to ferroptotic cell death pathways.","method":"Multi-omics (proteomics, metabolomics, transcriptomics) integration, LPS-induced ARDS mouse model, western blotting, ferroptosis-related biochemical assays (ROS, lipid peroxidation)","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mouse model with pharmacological inhibitor, but YWHAE's mechanistic role in ferroptosis is inferred from expression changes without direct functional manipulation","pmids":["40261442"],"is_preprint":false}],"current_model":"YWHAE encodes 14-3-3ε, a phosphoserine/phosphothreonine-binding adaptor protein that: (1) regulates neuronal migration and neurite morphogenesis by binding doublecortin (preventing its degradation) and interacting with NDEL1/LIS1; (2) controls autophagy via leucine deprivation-induced crotonylation at K73/K78, which releases PPM1B to dephosphorylate ULK1; (3) promotes mTORC1 signaling and protein synthesis in myeloma by binding and inhibiting the TSC1/TSC2 complex; (4) regulates cardiac NaV1.5 expression by binding and destabilizing TBX5 mRNA; (5) is essential for male fertility and spermatogenesis through regulation of GSK3 and PP1γ2 phosphorylation; and (6) when fused to NUTM2 oncoproteins (via chromosomal translocation), drives high-grade endometrial stromal sarcoma by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling to upregulate cyclin D1 and promote cell proliferation."},"narrative":{"mechanistic_narrative":"YWHAE encodes 14-3-3ε, a phosphopeptide-binding adaptor that governs cytoskeletal dynamics, growth signaling, and cell-fate decisions across neuronal and proliferative contexts [PMID:28173130, PMID:32187357, PMID:36999555]. In developing neurons it binds and stabilizes the microtubule-binding protein doublecortin, restraining microtubule invasion of nascent neurites; loss of 14-3-3ε increases neurite formation, and Ywhae-null mice display cortical thinning, corpus callosum dysgenesis, and hydrocephalus that mirror the neurodevelopmental phenotypes of human patients carrying heterozygous YWHAE loss-of-function variants [PMID:28173130, PMID:36999555]. As a signaling adaptor it promotes mTORC1 activity and protein synthesis by binding and inhibiting the TSC1/TSC2 complex, a role essential for the high protein load of multiple myeloma cells [PMID:32187357]. Its scaffolding output is tuned by post-translational modification: leucine deprivation drives lysine crotonylation at K73/K78 (reversed by HDAC7), which releases the phosphatase PPM1B to dephosphorylate ULK1 and activate autophagy [PMID:36628438]. 14-3-3ε also controls subcellular partitioning of effectors—retaining YAP1 in the cytoplasm—and acts in RNA-level regulation, binding and destabilizing TBX5 mRNA to suppress cardiac SCN5A/NaV1.5 expression and sodium current [PMID:38407929, PMID:38750908]. It is required for male fertility, with knockout sperm showing reduced GSK3 and PP1γ2 phosphorylation [PMID:32657535]. Oncogenically, the YWHAE-NUTM2 fusion produced by chromosomal translocation complexes with BRAF/RAF1 and YAP/TAZ to drive RAF/MEK/MAPK signaling and cyclin D1–dependent proliferation in high-grade endometrial stromal sarcoma [PMID:33947829].","teleology":[{"year":2016,"claim":"Established a concrete cytoskeletal mechanism for 14-3-3ε in neurodevelopment by showing it stabilizes doublecortin to control neurite outgrowth, moving beyond guilt-by-association to a defined binding partner and phenotype.","evidence":"Co-IP, 14-3-3ε flox knockout mice, neurite imaging, and DCX-knockdown rescue","pmids":["28173130"],"confidence":"High","gaps":["Does not define the phospho-site on DCX recognized by 14-3-3ε","Relationship to NDEL1/LIS1 pathway not addressed in this study"]},{"year":2016,"claim":"Addressed whether YWHAE constrains proliferation, finding it negatively regulates CDC25B and MYC in gastric cancer, framing it as a tumor-suppressive node in that context.","evidence":"siRNA knockdown of YWHAE/CDC25B/MYC with proliferation, invasion, migration assays and tumor expression analysis","pmids":["27863420"],"confidence":"Medium","gaps":["No direct binding assay establishing physical interaction","Mechanism of reciprocal MYC–YWHAE regulation undefined"]},{"year":2018,"claim":"Showed YWHAE is co-opted by a bacterial effector, binding H. pylori CagA to potentiate NF-κB activation, extending its adaptor role to host–pathogen signaling.","evidence":"Yeast two-hybrid, GST pull-down, Co-IP, immunolocalization, NF-κB reporter with OE/KD","pmids":["29106533"],"confidence":"Medium","gaps":["Binding interface and phospho-dependence not mapped","In vivo relevance to infection not tested"]},{"year":2020,"claim":"Resolved how 14-3-3ε drives growth signaling, demonstrating it inhibits the TSC1/TSC2 complex and promotes mTORC1 to sustain protein synthesis in myeloma.","evidence":"Co-IP for TSC1/TSC2 and mTORC1, KO/OE with quantitative protein-synthesis and immunoglobulin-secretion readouts and addback rescue","pmids":["32187357"],"confidence":"High","gaps":["Phospho-sites on TSC1/TSC2 mediating the interaction not defined","Whether effect generalizes beyond secretory tumor cells unclear"]},{"year":2020,"claim":"Defined an isoform-specific physiological requirement, showing Ywhae is essential for spermatogenesis and links to GSK3 and PP1γ2 phosphorylation in sperm.","evidence":"Conditional and global knockout mice, computer-assisted semen analysis, western blot for GSK3/PP1γ2 phosphorylation","pmids":["32657535"],"confidence":"High","gaps":["Direct substrate-binding mechanism for GSK3/PP1γ2 regulation not established","Step in spermatogenesis where 14-3-3ε acts not pinpointed"]},{"year":2021,"claim":"Established the oncogenic mechanism of the YWHAE-NUTM2 fusion, showing it scaffolds BRAF/RAF1 and YAP/TAZ to drive MAPK signaling and cyclin D1–dependent proliferation, with a synergistic MEK + CDK4/6 inhibitor vulnerability.","evidence":"Reciprocal Co-IP, fusion and cyclin D1 knockdown with phosphorylation/RB1/proliferation readouts, pharmacological inhibition","pmids":["33947829"],"confidence":"High","gaps":["How the fusion alters native 14-3-3ε binding specificity unresolved","Relative contributions of RAF/MAPK versus Hippo/YAP arms not dissected"]},{"year":2021,"claim":"Added a pro-tumorigenic interaction in ovarian cancer via HE4 (WFDC2), linking YWHAE to AKT/MAPK-driven invasion and survival.","evidence":"Co-IP, co-immunofluorescence, OE/KD with invasion/migration/proliferation/apoptosis assays and in vivo work","pmids":["34107979"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Whether HE4 binding is phospho-dependent unknown"]},{"year":2022,"claim":"Identified miR-29b-3p as a direct YWHAE 3'UTR repressor controlling the apoptotic balance (BAD/BAX/BCL-2) in prostate cancer.","evidence":"Dual-luciferase 3'UTR assay, miRNA OE, apoptosis-marker westerns, xenograft rescue","pmids":["35928803"],"confidence":"Medium","gaps":["How YWHAE biochemically modulates BAD phosphorylation not shown","Single cell-line context"]},{"year":2023,"claim":"Uncovered crotonylation as a metabolic switch on 14-3-3ε, with K73/K78 modification during leucine deprivation releasing PPM1B to dephosphorylate ULK1 and activate autophagy.","evidence":"Crotonylome MS, K73R/K78R mutagenesis, molecular dynamics, ULK1 phosphorylation and PPM1B interaction assays","pmids":["36628438"],"confidence":"High","gaps":["Crotonyl-CoA source and stoichiometry in vivo not quantified","Whether modification alters canonical phosphopeptide binding untested"]},{"year":2023,"claim":"Confirmed YWHAE haploinsufficiency causes a human neurodevelopmental disorder, with knockout mice recapitulating cortical, callosal, and ventricular defects of patients.","evidence":"Ywhae-/- mouse neuroanatomy and clinical phenotyping of 10 patients with heterozygous loss-of-function variants","pmids":["36999555"],"confidence":"High","gaps":["Molecular pathway linking 14-3-3ε loss to specific structural defects not dissected","Genotype–phenotype correlation across variants limited"]},{"year":2023,"claim":"Placed YWHAE transcriptionally downstream of NKD1 in colon cancer glucose metabolism, with NKD1 directly activating the YWHAE promoter.","evidence":"ChIP, dual-luciferase promoter assay, NKD1 KO with YWHAE-OE rescue of glucose uptake","pmids":["37202194"],"confidence":"Medium","gaps":["Mechanism by which YWHAE controls glucose uptake undefined","Single lab/cell system"]},{"year":2023,"claim":"Identified the TRIP13/YWHAE complex as a druggable node in myeloma, with the inhibitor DCZ5417 disrupting it to suppress ERK/MAPK signaling.","evidence":"Docking, pull-down, SPR, CETSA, ATPase assay, Co-IP, and genetic/pharmacological epistasis","pmids":["38012658"],"confidence":"Medium","gaps":["Functional consequence of the TRIP13–YWHAE interaction independent of drug not defined","Binding interface unmapped"]},{"year":2024,"claim":"Demonstrated a new RNA-regulatory function: 14-3-3ε binds and destabilizes TBX5 mRNA to suppress cardiac SCN5A/NaV1.5 and modulate sodium current and arrhythmia susceptibility.","evidence":"RNA immunoprecipitation, patch clamp, AAV9 knockdown in mice, ECG/echo, TBX5 epistasis","pmids":["38750908"],"confidence":"High","gaps":["Whether 14-3-3ε binds mRNA directly or via an adaptor not resolved","Mechanism of mRNA destabilization undefined"]},{"year":2024,"claim":"Showed YWHAE controls YAP1 cytoplasmic retention competitively, with ANKZF1 binding releasing YAP1 for nuclear pro-lymphangiogenic transcription in renal cancer.","evidence":"Co-IP, RIP, immunofluorescence, MS, site-specific mutagenesis, RNA-seq","pmids":["38407929"],"confidence":"Medium","gaps":["Phospho-dependence of the YWHAE–YAP1 interaction not detailed","Single lab/tumor context"]},{"year":2024,"claim":"Added miR-873-5p as another direct 3'UTR repressor of YWHAE, linking YWHAE to PI3K/AKT activation and gefitinib resistance in NSCLC.","evidence":"Dual-luciferase, RIP, pathway westerns, proliferation/migration assays with miRNA OE","pmids":["38363382"],"confidence":"Medium","gaps":["How YWHAE activates PI3K/AKT mechanistically not shown","Single cell-line context"]},{"year":2025,"claim":"Connected YWHAE to ferroptosis regulation, with m6A-driven stabilization (METTL3/IGF2BP2) promoting its expression and knockdown enhancing lipid-ROS and ferroptosis via SLC7A11 downregulation in hepatoblastoma.","evidence":"m6A-seq, m6A-RIP, Co-IP, in vitro/in vivo knockdown, lipid ROS/peroxide assays","pmids":["40074884"],"confidence":"Medium","gaps":["Direct mechanism linking YWHAE to SLC7A11 not established","Single tumor type"]},{"year":2025,"claim":"Reported YWHAE as a suppressor of osteogenic ALP expression in pre-adipocytes, hinting at a mesenchymal cell-fate role.","evidence":"siRNA knockdown in 3T3-L1 cells with ALP activity and transcriptomic/epigenomic profiling","pmids":["40792537"],"confidence":"Low","gaps":["Single siRNA knockdown with limited mechanistic depth","No direct target identified","Not validated in primary mesenchymal precursors"]},{"year":2025,"claim":"Associated YWHAE expression with ferroptotic lung injury in ARDS, where ferrostatin-1 reduced both injury and YWHAE levels.","evidence":"Multi-omics integration, LPS-induced ARDS mouse model, ferroptosis biochemical assays","pmids":["40261442"],"confidence":"Low","gaps":["Role inferred from expression changes without direct functional manipulation","Causal directionality versus ferroptosis unclear"]},{"year":null,"claim":"How a single adaptor integrates phosphopeptide binding, crotonylation, mRNA destabilization, and effector sequestration into context-specific outputs—and which interactions are direct versus indirect—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural model of partner selectivity across contexts","Direct versus adaptor-mediated RNA binding undefined","How crotonylation and phosphopeptide binding intersect functionally unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":["TSC1/TSC2 complex","YWHAE-NUTM2 fusion oncoprotein complex","TRIP13/YWHAE complex"],"partners":["DCX","TSC1","TSC2","PPM1B","YAP1","TRIP13","BRAF","WFDC2"],"other_free_text":[]}},"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":205,"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":169,"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":134,"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":100,"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":88,"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":65,"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":"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":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":56,"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":"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 process.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27863420","citation_count":42,"is_preprint":false},{"pmid":"26493387","id":"PMC_26493387","title":"BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26493387","citation_count":41,"is_preprint":false},{"pmid":"32317704","id":"PMC_32317704","title":"High-grade transformation of low-grade endometrial stromal sarcomas lacking YWHAE and BCOR genetic abnormalities.","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/32317704","citation_count":39,"is_preprint":false},{"pmid":"28173130","id":"PMC_28173130","title":"Regulation of neuronal morphogenesis by 14-3-3epsilon (Ywhae) via the microtubule binding protein, doublecortin.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28173130","citation_count":39,"is_preprint":false},{"pmid":"19635726","id":"PMC_19635726","title":"Deletion of YWHAE in a patient with periventricular heterotopias and pronounced corpus callosum hypoplasia.","date":"2009","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19635726","citation_count":36,"is_preprint":false},{"pmid":"31001932","id":"PMC_31001932","title":"YWHAE promotes proliferation, metastasis, and chemoresistance in breast cancer cells.","date":"2019","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31001932","citation_count":34,"is_preprint":false},{"pmid":"38407929","id":"PMC_38407929","title":"NAT10-mediated ac4C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell carcinoma by attenuating YWHAE-driven cytoplasmic retention of YAP1.","date":"2024","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38407929","citation_count":32,"is_preprint":false},{"pmid":"23035971","id":"PMC_23035971","title":"Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.","date":"2012","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23035971","citation_count":30,"is_preprint":false},{"pmid":"33947829","id":"PMC_33947829","title":"YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways.","date":"2021","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33947829","citation_count":25,"is_preprint":false},{"pmid":"31238337","id":"PMC_31238337","title":"YWHAE long non-coding RNA competes with miR-323a-3p and miR-532-5p through activating K-Ras/Erk1/2 and PI3K/Akt signaling pathways in HCT116 cells.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31238337","citation_count":24,"is_preprint":false},{"pmid":"26172220","id":"PMC_26172220","title":"Epistatic and gene wide effects in YWHA and aromatic amino hydroxylase genes across ADHD and other common neuropsychiatric disorders: Association with YWHAE.","date":"2015","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26172220","citation_count":24,"is_preprint":false},{"pmid":"27154512","id":"PMC_27154512","title":"Molecular Cytogenetic Analysis of JAZF1, PHF1, and YWHAE in Endometrial Stromal Tumors: Discovery of Genetic Complexity by Fluorescence in Situ Hybridization.","date":"2016","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/27154512","citation_count":23,"is_preprint":false},{"pmid":"35053800","id":"PMC_35053800","title":"Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε).","date":"2021","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35053800","citation_count":20,"is_preprint":false},{"pmid":"35515139","id":"PMC_35515139","title":"RNA-Binding Protein COL14A1, TNS1, NUSAP1 and YWHAE Are Valid Biomarkers to Predict Peritoneal Metastasis in Gastric Cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35515139","citation_count":20,"is_preprint":false},{"pmid":"38001345","id":"PMC_38001345","title":"Comprehensive analysis of the function of helicobacter-associated ferroptosis gene YWHAE in gastric cancer through multi-omics integration, molecular docking, and machine learning.","date":"2023","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/38001345","citation_count":20,"is_preprint":false},{"pmid":"34107979","id":"PMC_34107979","title":"YWHAE as an HE4 interacting protein can influence the malignant behaviour of ovarian cancer by regulating the PI3K/AKT and MAPK pathways.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34107979","citation_count":20,"is_preprint":false},{"pmid":"24125656","id":"PMC_24125656","title":"Breakages at YWHAE, FAM22A, and FAM22B loci in uterine angiosarcoma: a case report with immunohistochemical and genetic analysis.","date":"2013","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/24125656","citation_count":19,"is_preprint":false},{"pmid":"32187357","id":"PMC_32187357","title":"YWHAE/14-3-3ε expression impacts the protein load, contributing to proteasome inhibitor sensitivity in multiple myeloma.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32187357","citation_count":18,"is_preprint":false},{"pmid":"23140658","id":"PMC_23140658","title":"Polymorphisms and haplotypes in the YWHAE gene increase susceptibility to bipolar disorder in Chinese Han population.","date":"2012","source":"The Journal of clinical psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23140658","citation_count":17,"is_preprint":false},{"pmid":"24561237","id":"PMC_24561237","title":"The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and orbitofrontal sulcogyral pattern in patients with schizophrenia and healthy subjects.","date":"2014","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24561237","citation_count":17,"is_preprint":false},{"pmid":"28542865","id":"PMC_28542865","title":"Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.","date":"2017","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28542865","citation_count":16,"is_preprint":false},{"pmid":"36628438","id":"PMC_36628438","title":"YWHAE/14-3-3ε crotonylation regulates leucine deprivation-induced autophagy.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36628438","citation_count":15,"is_preprint":false},{"pmid":"25105667","id":"PMC_25105667","title":"The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and brain morphology in schizophrenia: a voxel-based morphometric study.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25105667","citation_count":15,"is_preprint":false},{"pmid":"34758342","id":"PMC_34758342","title":"A translational study: Involvement of miR-21-5p in development and maintenance of neuropathic pain via immune-related targets CCL5 and YWHAE.","date":"2021","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34758342","citation_count":14,"is_preprint":false},{"pmid":"26542179","id":"PMC_26542179","title":"The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26542179","citation_count":14,"is_preprint":false},{"pmid":"30252726","id":"PMC_30252726","title":"YWHAE-NUTM2A/B Translocated High-grade Endometrial Stromal Sarcoma Commonly Expresses CD56 and CD99.","date":"2019","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/30252726","citation_count":14,"is_preprint":false},{"pmid":"23982958","id":"PMC_23982958","title":"YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment.","date":"2013","source":"Journal of neurovirology","url":"https://pubmed.ncbi.nlm.nih.gov/23982958","citation_count":14,"is_preprint":false},{"pmid":"32657535","id":"PMC_32657535","title":"The protein YWHAE (14-3-3 epsilon) in spermatozoa is essential for male fertility.","date":"2020","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/32657535","citation_count":12,"is_preprint":false},{"pmid":"36999555","id":"PMC_36999555","title":"YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36999555","citation_count":11,"is_preprint":false},{"pmid":"38012658","id":"PMC_38012658","title":"The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38012658","citation_count":11,"is_preprint":false},{"pmid":"32323081","id":"PMC_32323081","title":"17p13.3 microdeletion including YWHAE and CRK genes: towards a clinical characterization.","date":"2020","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/32323081","citation_count":11,"is_preprint":false},{"pmid":"27232341","id":"PMC_27232341","title":"Normalization of qPCR in platelets - YWHAE a potential genericreference gene.","date":"2016","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/27232341","citation_count":11,"is_preprint":false},{"pmid":"37032555","id":"PMC_37032555","title":"Uterine Endometrial Stromal Tumors With Pure Low-Grade Morphology Harboring YWHAE::NUTM2 Fusions: Report of a Case Series Emphasizing Potential for High-Grade Transformation and Aggressive Behavior.","date":"2023","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37032555","citation_count":11,"is_preprint":false},{"pmid":"27171540","id":"PMC_27171540","title":"An Unusual Case of YWHAE-NUTM2A/B Endometrial Stromal Sarcoma With Confinement to the Endometrium and Lack of High-Grade Morphology.","date":"2017","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/27171540","citation_count":11,"is_preprint":false},{"pmid":"36433683","id":"PMC_36433683","title":"Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36433683","citation_count":9,"is_preprint":false},{"pmid":"35116456","id":"PMC_35116456","title":"KRAS, YWHAE, SP1 and MSRA as biomarkers in endometrial cancer.","date":"2021","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35116456","citation_count":9,"is_preprint":false},{"pmid":"29106533","id":"PMC_29106533","title":"YWHAE is a novel interaction partner of Helicobacter pylori CagA.","date":"2018","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29106533","citation_count":9,"is_preprint":false},{"pmid":"31543780","id":"PMC_31543780","title":"Neonatal Soft Tissue Sarcoma with YWHAE-NUTM2B Fusion.","date":"2019","source":"Case reports in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31543780","citation_count":9,"is_preprint":false},{"pmid":"35928803","id":"PMC_35928803","title":"miR-29b-3p inhibits 22Rv1 prostate cancer cell proliferation through the YWHAE/BCL-2 regulatory axis.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35928803","citation_count":8,"is_preprint":false},{"pmid":"21184166","id":"PMC_21184166","title":"No association of the YWHAE gene with schizophrenia, major depressive disorder or bipolar disorder in the Han Chinese population.","date":"2010","source":"Behavior genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21184166","citation_count":8,"is_preprint":false},{"pmid":"28414084","id":"PMC_28414084","title":"The YWHAE gene confers risk to major depressive disorder in the male group of Chinese Han population.","date":"2017","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28414084","citation_count":8,"is_preprint":false},{"pmid":"38363382","id":"PMC_38363382","title":"The novel miR-873-5p-YWHAE-PI3K/AKT axis is involved in non-small cell lung cancer progression and chemoresistance by mediating autophagy.","date":"2024","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38363382","citation_count":7,"is_preprint":false},{"pmid":"31244373","id":"PMC_31244373","title":"Functional study of 14-3-3 protein epsilon (YWHAE) in keratinocytes: microarray integrating bioinformatics approaches.","date":"2019","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/31244373","citation_count":7,"is_preprint":false},{"pmid":"34843125","id":"PMC_34843125","title":"JAZF1, YWHAE and BCOR gene translocation in primary extrauterine low-grade and high-grade endometrial stromal sarcomas.","date":"2022","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34843125","citation_count":5,"is_preprint":false},{"pmid":"38361148","id":"PMC_38361148","title":"Exosomes from Intrahepatic Cholestasis of Pregnancy Induce Cell Apoptosis Through the miRNA-6891-5p/YWHAE Pathway.","date":"2024","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38361148","citation_count":5,"is_preprint":false},{"pmid":"27142911","id":"PMC_27142911","title":"[Endometrial stromal sarcoma: morphologic features and detection of JAZF1-SUZ12 and YWHAE FAM22 fusion genes].","date":"2016","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27142911","citation_count":5,"is_preprint":false},{"pmid":"22887762","id":"PMC_22887762","title":"Expression analysis of a 17p terminal deletion, including YWHAE, but not PAFAH1B1, associated with normal brain structure on MRI in a young girl.","date":"2012","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22887762","citation_count":5,"is_preprint":false},{"pmid":"40261442","id":"PMC_40261442","title":"Multi-omics integration reveals YWHAE as a key mediator of ferroptosis in ARDS.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40261442","citation_count":4,"is_preprint":false},{"pmid":"28288693","id":"PMC_28288693","title":"Uterine epithelioid leiomyosarcoma with c-kit expression and YWHAE gene rearrangement: a case report of a diagnostic pitfall of uterine sarcoma.","date":"2017","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28288693","citation_count":4,"is_preprint":false},{"pmid":"35326370","id":"PMC_35326370","title":"Correction: Liu et al. Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε). Brain Sci. 2022, 12, 56.","date":"2022","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35326370","citation_count":4,"is_preprint":false},{"pmid":"24450199","id":"PMC_24450199","title":"[Association of YWHAE gene polymorphism with suicidal behavior].","date":"2013","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/24450199","citation_count":4,"is_preprint":false},{"pmid":"35545369","id":"PMC_35545369","title":"Genetic variation of YWHAE gene-\"Switch\" of disease control.","date":"2022","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35545369","citation_count":3,"is_preprint":false},{"pmid":"40386277","id":"PMC_40386277","title":"YWHAE affects proliferation, migration and apoptosis of colorectal cancer by regulating extracellular vesicles secretion and Wnt/β-catenin signaling pathway.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40386277","citation_count":3,"is_preprint":false},{"pmid":"31607703","id":"PMC_31607703","title":"Utility of YWHAE fluorescent in-situ hybridisation in mesenchymal tumors of uterus- An initial experience from tertiary oncology centre in India.","date":"2019","source":"Indian journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31607703","citation_count":3,"is_preprint":false},{"pmid":"40074884","id":"PMC_40074884","title":"N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40074884","citation_count":2,"is_preprint":false},{"pmid":"38750908","id":"PMC_38750908","title":"14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel NaV1.5.","date":"2024","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/38750908","citation_count":2,"is_preprint":false},{"pmid":"37533428","id":"PMC_37533428","title":"High-grade endometrial stromal sarcoma with YWHAE-NUTM2B fusion gene abnormality identified after 10 years of recurrent pulmonary metastases: A case report.","date":"2023","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37533428","citation_count":2,"is_preprint":false},{"pmid":"37202194","id":"PMC_37202194","title":"[NKD1 promotes glucose uptake in colon cancer cells by activating YWHAE transcription].","date":"2023","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/37202194","citation_count":1,"is_preprint":false},{"pmid":"41218078","id":"PMC_41218078","title":"Behavioral analyses of a forebrain glutamatergic neuron specific Ywhae conditional knockout mouse model.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41218078","citation_count":1,"is_preprint":false},{"pmid":"35814390","id":"PMC_35814390","title":"Case Report: An Adolescent Soft Tissue Sarcoma With YWHAE-NUTM2B Fusion Is Effectively Treated With Combined Therapy of Epirubicin and Anlotinib.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35814390","citation_count":1,"is_preprint":false},{"pmid":"40792537","id":"PMC_40792537","title":"Synergistic epigenetic modulation by 5-aza-2'-deoxycytidine and Wnt3a drives osteogenic trans-differentiation of 3T3-L1 pre-adipocytes through Ywhah and Ywhae.","date":"2025","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/40792537","citation_count":0,"is_preprint":false},{"pmid":"41644425","id":"PMC_41644425","title":"[YWHAE-rearranged clear cell sarcoma of kidney: a clinicopathological analysis of seven cases].","date":"2026","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41644425","citation_count":0,"is_preprint":false},{"pmid":"41983776","id":"PMC_41983776","title":"MiR-4261 targeted YWHAE/CAST/GPX1 impairs the calcium regulatory function of PMCA4 in erythrocytes of myeloma.","date":"2026","source":"Indian journal of pathology & microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41983776","citation_count":0,"is_preprint":false},{"pmid":"41052351","id":"PMC_41052351","title":"Congenital Undifferentiated Retroperitoneal Sarcoma With YWHAE::NUTM2B Fusion From the Abdomen to the Brain.","date":"2025","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41052351","citation_count":0,"is_preprint":false},{"pmid":"41656856","id":"PMC_41656856","title":"An adult patient with pulmonary atresia with ventricular septal defect and chromosome 17p13.3 microdeletion including YWHAE gene.","date":"2026","source":"Cardiology in the young","url":"https://pubmed.ncbi.nlm.nih.gov/41656856","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.01.635574","title":"Genome-wide identification and characterization of QTLs for transcriptional noise in human midbrain cells","date":"2025-02-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.01.635574","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44317,"output_tokens":5093,"usd":0.104673,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13368,"output_tokens":5657,"usd":0.104133,"stage2_stop_reason":"end_turn"},"total_usd":0.208806,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"14-3-3ε (YWHAE) binds to the microtubule-binding protein doublecortin (DCX), preventing its degradation. Overexpression of 14-3-3ε disrupts neurite formation by preventing microtubule invasion into primitive neurites, an effect rescuable by DCX knockdown. Conversely, 14-3-3ε deficiency (flox knockout) increases neurite formation.\",\n      \"method\": \"Co-immunoprecipitation/binding assay, in vitro and in vivo (14-3-3ε flox mice) techniques, neurite formation imaging, rescue by siRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assay, in vivo knockout model, and rescue experiment; multiple orthogonal methods in single study\",\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. Cyclin D1 knockdown dephosphorylates RB1 and inhibits proliferation. MEK and CDK4/6 inhibitors have synergistic anti-proliferative effects in HG-ESS.\",\n      \"method\": \"Co-immunoprecipitation (BRAF/RAF1 and YAP/TAZ), siRNA knockdown of YWHAE-NUTM2 and cyclin D1 with proliferation/phosphorylation readouts, pharmacological inhibition\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, knockdown with multiple downstream readouts (phosphorylation, cyclin D1, RB1, proliferation), pharmacological validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33947829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YWHAE/14-3-3ε undergoes lysine crotonylation at K73 and K78 during leucine deprivation-induced autophagy. Blocking crotonylation (K73R/K78R mutants) attenuates autophagy. Crotonylation of YWHAE releases PPM1B, which then dephosphorylates ULK1 to activate autophagy. Decrotonylation of YWHAE is mediated by HDAC7, whose activity is inhibited by leucine deprivation.\",\n      \"method\": \"Crotonylome mass spectrometry, site-directed mutagenesis (K73R/K78R), molecular dynamics simulation, biochemical assays for ULK1 phosphorylation and PPM1B interaction\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis, mass spectrometry-based PTM identification, molecular dynamics, functional autophagy readouts; multiple orthogonal methods in single study\",\n      \"pmids\": [\"36628438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"14-3-3ε (YWHAE) promotes translation initiation and protein synthesis in multiple myeloma cells through binding and inhibition of the TSC1/TSC2 complex, and directly interacts with and promotes phosphorylation of mTORC1. 14-3-3ε depletion reduces protein synthesis by ~50% and decreases immunoglobulin light chain secretion; overexpression or addback restores protein synthesis and protein load.\",\n      \"method\": \"Co-immunoprecipitation (TSC1/TSC2, mTORC1), siRNA knockdown and overexpression with protein synthesis measurement, immunoglobulin secretion assay, knockout with addback\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for TSC1/TSC2 and mTORC1 interactions, KO/OE with quantitative protein synthesis readouts and rescue; multiple orthogonal methods\",\n      \"pmids\": [\"32187357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YWHAE silencing in gastric cancer cells upregulates CDC25B and MYC expression, leading to increased cell proliferation, invasion, and migration. YWHAE acts as a negative regulator of the cyclin phosphatase CDC25B and the MYC oncogene. Conversely, MYC induces CDC25B and reduces YWHAE expression.\",\n      \"method\": \"siRNA knockdown of YWHAE, CDC25B, and MYC in gastric cancer cell lines; proliferation, invasion, migration assays; expression analysis in cell lines and tumor samples\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with cellular phenotypic readouts and reciprocal regulation; single lab, no direct binding assay\",\n      \"pmids\": [\"27863420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YWHAE interacts directly with H. pylori virulence factor CagA. This interaction was identified by yeast two-hybrid screen and validated by GST pull-down, co-immunoprecipitation, and immunolocalization. Overexpression of YWHAE promotes CagA-mediated NF-κB activation; knockdown of YWHAE inhibits NF-κB activation by CagA.\",\n      \"method\": \"GAL4 yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, immunolocalization, YWHAE overexpression/knockdown with NF-κB reporter assay\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus Co-IP plus functional NF-κB readout with OE/KD; single lab, multiple orthogonal binding methods\",\n      \"pmids\": [\"29106533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANKZF1 interacts with YWHAE to competitively inhibit YWHAE-driven cytoplasmic retention of YAP1, leading to nuclear import of YAP1 and transcriptional activation of pro-lymphangiogenic factors in clear-cell renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, mass spectrometry, site-specific mutation analyses, RNA sequencing\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and immunofluorescence to validate ANKZF1-YWHAE interaction and YAP1 localization, supported by mutagenesis; single lab\",\n      \"pmids\": [\"38407929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"14-3-3ε (YWHAE) is essential for male fertility: it is expressed in spermatozoa (unlike 14-3-3η), and testis-specific and global knockout of Ywhae in mice causes infertility with low sperm count, higher sperm abnormalities, and reduced sperm motility. Knockout spermatozoa show reduced phosphorylation of glycogen synthase kinase 3 and PP1γ2.\",\n      \"method\": \"Conditional knockout (CKO) and global knockout (GKO) mouse models, computer-assisted semen analysis, immunohistochemistry, western blot for GSK3 and PP1γ2 phosphorylation\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean isoform-specific knockout with defined fertility and sperm motility phenotype, biochemical substrate phosphorylation readout; replicated in CKO and GKO models\",\n      \"pmids\": [\"32657535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DCZ5417 (a norcantharidin derivative) targets TRIP13 ATPase and disrupts the TRIP13/YWHAE protein complex, thereby inhibiting ERK/MAPK signaling and suppressing multiple myeloma cell proliferation. The anti-myeloma activity depends on TRIP13.\",\n      \"method\": \"Molecular docking, pull-down assay, surface plasmon resonance binding assay, cellular thermal shift assay, ATPase assay, Co-IP for TRIP13/YWHAE complex, genetic and pharmacological epistasis\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple direct binding methods (pull-down, SPR, CETSA) plus functional complex disruption readout; single lab\",\n      \"pmids\": [\"38012658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"14-3-3ε/YWHAE negatively regulates cardiac NaV1.5 expression by binding to and destabilizing TBX5 mRNA (a transcription factor for SCN5A), thereby decreasing SCN5A mRNA levels and sodium current density. YWHAE knockdown in mice (via AAV9) increases SCN5A mRNA and sodium current and leads to shorter R-R intervals and higher prevalence of premature ventricular contractions.\",\n      \"method\": \"Western blotting, patch clamping, RT-PCR, RNA immunoprecipitation (14-3-3ε with TBX5 mRNA), AAV9-mediated YWHAE knockdown in mice, electrocardiogram, echocardiography; TBX5 knockdown epistasis\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation identifying mRNA binding, electrophysiology, in vivo AAV knockdown, epistasis with TBX5; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38750908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"N6-methyladenosine (m6A) modification of YWHAE mRNA by METTL3, read by IGF2BP2, enhances YWHAE mRNA stability and promotes its expression in hepatoblastoma. YWHAE knockdown increases lipid ROS and peroxides, enhancing ferroptosis susceptibility, partly through downregulation of SLC7A11.\",\n      \"method\": \"m6A sequencing, RNA sequencing, m6A-RIP, co-immunoprecipitation, in vitro and in vivo knockdown studies, lipid ROS/peroxide assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP for writer/reader identification, in vitro and in vivo KD with ferroptosis readouts; single lab, multiple methods\",\n      \"pmids\": [\"40074884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NKD1 protein binds to the YWHAE gene promoter and activates YWHAE transcription in colon cancer cells. NKD1 overexpression increases YWHAE mRNA and protein; NKD1 knockout reduces both. YWHAE overexpression rescues the glucose uptake deficit caused by NKD1 knockout, placing YWHAE downstream of NKD1 in glucose metabolism regulation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay, RT-qPCR, western blot, immunofluorescence, glucose uptake assay, NKD1 knockout and YWHAE overexpression rescue\",\n      \"journal\": \"Journal of Southern Medical University\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for direct promoter binding, functional rescue experiment; single lab\",\n      \"pmids\": [\"37202194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ywhae (14-3-3ε) knockdown in 3T3-L1 pre-adipocytes enhances Alpl (alkaline phosphatase) expression even without DNA demethylation treatment, identifying YWHAE/Ywhae as a suppressor of osteogenic gene expression in mesenchymal precursors.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 cells, ALP activity assay, transcriptomic and epigenomic profiling\",\n      \"journal\": \"Epigenomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown with ALP readout; single lab, limited mechanistic depth\",\n      \"pmids\": [\"40792537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-29b-3p targets the 3'UTR of YWHAE mRNA (validated by dual luciferase assay) and inhibits YWHAE expression, resulting in decreased p-BAD/BAD ratio and increased BAX/BCL-2 ratio in 22Rv1 prostate cancer cells, promoting apoptosis. YWHAE overexpression reverses the anti-proliferative effects of miR-29b-3p.\",\n      \"method\": \"Dual luciferase reporter assay (miR-29b-3p targeting YWHAE 3'UTR), siRNA/miRNA overexpression, western blot (BAD, BAX, BCL-2, caspase-3), proliferation/apoptosis assays, in vivo xenograft rescue\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting validated by luciferase, multiple apoptosis markers, in vivo rescue; single lab\",\n      \"pmids\": [\"35928803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YWHAE interacts with HE4 (WFDC2) in ovarian cancer cells, as demonstrated by co-immunoprecipitation and co-immunofluorescence. YWHAE overexpression enhances invasion, migration, and proliferation while inhibiting apoptosis of ovarian cancer cells through the AKT and MAPK signaling pathways.\",\n      \"method\": \"Co-immunoprecipitation, western blot, cellular immunofluorescence, YWHAE overexpression/knockdown with invasion/migration/proliferation/apoptosis assays, in vivo experiments\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for HE4 interaction, functional assays with OE/KD; single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"34107979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-873-5p directly targets YWHAE 3'UTR (validated by dual-luciferase assay and RIP), suppressing YWHAE expression and inhibiting NSCLC cell proliferation, migration, invasion, and EMT. YWHAE promotes PI3K/AKT pathway activation; miR-873-5p overexpression inhibits the YWHAE-mediated PI3K/AKT signaling cascade and reverses gefitinib resistance by inducing autophagy.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), western blot (YWHAE, PI3K, AKT), CCK8, colony formation, Transwell, miR-873-5p overexpression\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase and RIP for direct targeting, pathway western blots, functional rescue; single lab\",\n      \"pmids\": [\"38363382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ywhae (14-3-3ε) knockout mice show brain structural defects including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus, paralleling neurodevelopmental brain abnormalities seen in human patients with YWHAE loss-of-function variants.\",\n      \"method\": \"Ywhae-/- mouse knockout, neuroanatomical studies (histology, brain imaging), clinical phenotyping of 10 human patients with heterozygous YWHAE loss-of-function variants\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mouse knockout with defined neuroanatomical phenotypes replicated in human patients; translational replication across species\",\n      \"pmids\": [\"36999555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YWHAE is identified as a ferroptosis-associated gene upregulated in ARDS. In an LPS-induced ARDS mouse model, the ferroptosis inhibitor ferrostatin-1 attenuates lung injury and downregulates YWHAE expression, suggesting YWHAE expression is linked to ferroptotic cell death pathways.\",\n      \"method\": \"Multi-omics (proteomics, metabolomics, transcriptomics) integration, LPS-induced ARDS mouse model, western blotting, ferroptosis-related biochemical assays (ROS, lipid peroxidation)\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mouse model with pharmacological inhibitor, but YWHAE's mechanistic role in ferroptosis is inferred from expression changes without direct functional manipulation\",\n      \"pmids\": [\"40261442\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YWHAE encodes 14-3-3ε, a phosphoserine/phosphothreonine-binding adaptor protein that: (1) regulates neuronal migration and neurite morphogenesis by binding doublecortin (preventing its degradation) and interacting with NDEL1/LIS1; (2) controls autophagy via leucine deprivation-induced crotonylation at K73/K78, which releases PPM1B to dephosphorylate ULK1; (3) promotes mTORC1 signaling and protein synthesis in myeloma by binding and inhibiting the TSC1/TSC2 complex; (4) regulates cardiac NaV1.5 expression by binding and destabilizing TBX5 mRNA; (5) is essential for male fertility and spermatogenesis through regulation of GSK3 and PP1γ2 phosphorylation; and (6) when fused to NUTM2 oncoproteins (via chromosomal translocation), drives high-grade endometrial stromal sarcoma by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling to upregulate cyclin D1 and promote cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YWHAE encodes 14-3-3\\u03b5, a phosphopeptide-binding adaptor that governs cytoskeletal dynamics, growth signaling, and cell-fate decisions across neuronal and proliferative contexts [#0, #3, #16]. In developing neurons it binds and stabilizes the microtubule-binding protein doublecortin, restraining microtubule invasion of nascent neurites; loss of 14-3-3\\u03b5 increases neurite formation, and Ywhae-null mice display cortical thinning, corpus callosum dysgenesis, and hydrocephalus that mirror the neurodevelopmental phenotypes of human patients carrying heterozygous YWHAE loss-of-function variants [#0, #16]. As a signaling adaptor it promotes mTORC1 activity and protein synthesis by binding and inhibiting the TSC1/TSC2 complex, a role essential for the high protein load of multiple myeloma cells [#3]. Its scaffolding output is tuned by post-translational modification: leucine deprivation drives lysine crotonylation at K73/K78 (reversed by HDAC7), which releases the phosphatase PPM1B to dephosphorylate ULK1 and activate autophagy [#2]. 14-3-3\\u03b5 also controls subcellular partitioning of effectors\\u2014retaining YAP1 in the cytoplasm\\u2014and acts in RNA-level regulation, binding and destabilizing TBX5 mRNA to suppress cardiac SCN5A/NaV1.5 expression and sodium current [#6, #9]. It is required for male fertility, with knockout sperm showing reduced GSK3 and PP1\\u03b32 phosphorylation [#7]. Oncogenically, the YWHAE-NUTM2 fusion produced by chromosomal translocation complexes with BRAF/RAF1 and YAP/TAZ to drive RAF/MEK/MAPK signaling and cyclin D1\\u2013dependent proliferation in high-grade endometrial stromal sarcoma [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a concrete cytoskeletal mechanism for 14-3-3\\u03b5 in neurodevelopment by showing it stabilizes doublecortin to control neurite outgrowth, moving beyond guilt-by-association to a defined binding partner and phenotype.\",\n      \"evidence\": \"Co-IP, 14-3-3\\u03b5 flox knockout mice, neurite imaging, and DCX-knockdown rescue\",\n      \"pmids\": [\"28173130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the phospho-site on DCX recognized by 14-3-3\\u03b5\", \"Relationship to NDEL1/LIS1 pathway not addressed in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Addressed whether YWHAE constrains proliferation, finding it negatively regulates CDC25B and MYC in gastric cancer, framing it as a tumor-suppressive node in that context.\",\n      \"evidence\": \"siRNA knockdown of YWHAE/CDC25B/MYC with proliferation, invasion, migration assays and tumor expression analysis\",\n      \"pmids\": [\"27863420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding assay establishing physical interaction\", \"Mechanism of reciprocal MYC\\u2013YWHAE regulation undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed YWHAE is co-opted by a bacterial effector, binding H. pylori CagA to potentiate NF-\\u03baB activation, extending its adaptor role to host\\u2013pathogen signaling.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, Co-IP, immunolocalization, NF-\\u03baB reporter with OE/KD\",\n      \"pmids\": [\"29106533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface and phospho-dependence not mapped\", \"In vivo relevance to infection not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how 14-3-3\\u03b5 drives growth signaling, demonstrating it inhibits the TSC1/TSC2 complex and promotes mTORC1 to sustain protein synthesis in myeloma.\",\n      \"evidence\": \"Co-IP for TSC1/TSC2 and mTORC1, KO/OE with quantitative protein-synthesis and immunoglobulin-secretion readouts and addback rescue\",\n      \"pmids\": [\"32187357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-sites on TSC1/TSC2 mediating the interaction not defined\", \"Whether effect generalizes beyond secretory tumor cells unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an isoform-specific physiological requirement, showing Ywhae is essential for spermatogenesis and links to GSK3 and PP1\\u03b32 phosphorylation in sperm.\",\n      \"evidence\": \"Conditional and global knockout mice, computer-assisted semen analysis, western blot for GSK3/PP1\\u03b32 phosphorylation\",\n      \"pmids\": [\"32657535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate-binding mechanism for GSK3/PP1\\u03b32 regulation not established\", \"Step in spermatogenesis where 14-3-3\\u03b5 acts not pinpointed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the oncogenic mechanism of the YWHAE-NUTM2 fusion, showing it scaffolds BRAF/RAF1 and YAP/TAZ to drive MAPK signaling and cyclin D1\\u2013dependent proliferation, with a synergistic MEK + CDK4/6 inhibitor vulnerability.\",\n      \"evidence\": \"Reciprocal Co-IP, fusion and cyclin D1 knockdown with phosphorylation/RB1/proliferation readouts, pharmacological inhibition\",\n      \"pmids\": [\"33947829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the fusion alters native 14-3-3\\u03b5 binding specificity unresolved\", \"Relative contributions of RAF/MAPK versus Hippo/YAP arms not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added a pro-tumorigenic interaction in ovarian cancer via HE4 (WFDC2), linking YWHAE to AKT/MAPK-driven invasion and survival.\",\n      \"evidence\": \"Co-IP, co-immunofluorescence, OE/KD with invasion/migration/proliferation/apoptosis assays and in vivo work\",\n      \"pmids\": [\"34107979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Whether HE4 binding is phospho-dependent unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified miR-29b-3p as a direct YWHAE 3'UTR repressor controlling the apoptotic balance (BAD/BAX/BCL-2) in prostate cancer.\",\n      \"evidence\": \"Dual-luciferase 3'UTR assay, miRNA OE, apoptosis-marker westerns, xenograft rescue\",\n      \"pmids\": [\"35928803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How YWHAE biochemically modulates BAD phosphorylation not shown\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered crotonylation as a metabolic switch on 14-3-3\\u03b5, with K73/K78 modification during leucine deprivation releasing PPM1B to dephosphorylate ULK1 and activate autophagy.\",\n      \"evidence\": \"Crotonylome MS, K73R/K78R mutagenesis, molecular dynamics, ULK1 phosphorylation and PPM1B interaction assays\",\n      \"pmids\": [\"36628438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crotonyl-CoA source and stoichiometry in vivo not quantified\", \"Whether modification alters canonical phosphopeptide binding untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed YWHAE haploinsufficiency causes a human neurodevelopmental disorder, with knockout mice recapitulating cortical, callosal, and ventricular defects of patients.\",\n      \"evidence\": \"Ywhae-/- mouse neuroanatomy and clinical phenotyping of 10 patients with heterozygous loss-of-function variants\",\n      \"pmids\": [\"36999555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking 14-3-3\\u03b5 loss to specific structural defects not dissected\", \"Genotype\\u2013phenotype correlation across variants limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed YWHAE transcriptionally downstream of NKD1 in colon cancer glucose metabolism, with NKD1 directly activating the YWHAE promoter.\",\n      \"evidence\": \"ChIP, dual-luciferase promoter assay, NKD1 KO with YWHAE-OE rescue of glucose uptake\",\n      \"pmids\": [\"37202194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which YWHAE controls glucose uptake undefined\", \"Single lab/cell system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the TRIP13/YWHAE complex as a druggable node in myeloma, with the inhibitor DCZ5417 disrupting it to suppress ERK/MAPK signaling.\",\n      \"evidence\": \"Docking, pull-down, SPR, CETSA, ATPase assay, Co-IP, and genetic/pharmacological epistasis\",\n      \"pmids\": [\"38012658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the TRIP13\\u2013YWHAE interaction independent of drug not defined\", \"Binding interface unmapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a new RNA-regulatory function: 14-3-3\\u03b5 binds and destabilizes TBX5 mRNA to suppress cardiac SCN5A/NaV1.5 and modulate sodium current and arrhythmia susceptibility.\",\n      \"evidence\": \"RNA immunoprecipitation, patch clamp, AAV9 knockdown in mice, ECG/echo, TBX5 epistasis\",\n      \"pmids\": [\"38750908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 14-3-3\\u03b5 binds mRNA directly or via an adaptor not resolved\", \"Mechanism of mRNA destabilization undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed YWHAE controls YAP1 cytoplasmic retention competitively, with ANKZF1 binding releasing YAP1 for nuclear pro-lymphangiogenic transcription in renal cancer.\",\n      \"evidence\": \"Co-IP, RIP, immunofluorescence, MS, site-specific mutagenesis, RNA-seq\",\n      \"pmids\": [\"38407929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phospho-dependence of the YWHAE\\u2013YAP1 interaction not detailed\", \"Single lab/tumor context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added miR-873-5p as another direct 3'UTR repressor of YWHAE, linking YWHAE to PI3K/AKT activation and gefitinib resistance in NSCLC.\",\n      \"evidence\": \"Dual-luciferase, RIP, pathway westerns, proliferation/migration assays with miRNA OE\",\n      \"pmids\": [\"38363382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How YWHAE activates PI3K/AKT mechanistically not shown\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected YWHAE to ferroptosis regulation, with m6A-driven stabilization (METTL3/IGF2BP2) promoting its expression and knockdown enhancing lipid-ROS and ferroptosis via SLC7A11 downregulation in hepatoblastoma.\",\n      \"evidence\": \"m6A-seq, m6A-RIP, Co-IP, in vitro/in vivo knockdown, lipid ROS/peroxide assays\",\n      \"pmids\": [\"40074884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking YWHAE to SLC7A11 not established\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported YWHAE as a suppressor of osteogenic ALP expression in pre-adipocytes, hinting at a mesenchymal cell-fate role.\",\n      \"evidence\": \"siRNA knockdown in 3T3-L1 cells with ALP activity and transcriptomic/epigenomic profiling\",\n      \"pmids\": [\"40792537\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA knockdown with limited mechanistic depth\", \"No direct target identified\", \"Not validated in primary mesenchymal precursors\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated YWHAE expression with ferroptotic lung injury in ARDS, where ferrostatin-1 reduced both injury and YWHAE levels.\",\n      \"evidence\": \"Multi-omics integration, LPS-induced ARDS mouse model, ferroptosis biochemical assays\",\n      \"pmids\": [\"40261442\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Role inferred from expression changes without direct functional manipulation\", \"Causal directionality versus ferroptosis unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single adaptor integrates phosphopeptide binding, crotonylation, mRNA destabilization, and effector sequestration into context-specific outputs\\u2014and which interactions are direct versus indirect\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural model of partner selectivity across contexts\", \"Direct versus adaptor-mediated RNA binding undefined\", \"How crotonylation and phosphopeptide binding intersect functionally unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"TSC1/TSC2 complex\",\n      \"YWHAE-NUTM2 fusion oncoprotein complex\",\n      \"TRIP13/YWHAE complex\"\n    ],\n    \"partners\": [\n      \"DCX\",\n      \"TSC1\",\n      \"TSC2\",\n      \"PPM1B\",\n      \"YAP1\",\n      \"TRIP13\",\n      \"BRAF\",\n      \"WFDC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}