{"gene":"YWHAH","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2006,"finding":"YWHAH (14-3-3 eta) physically interacts with Gremlin 1 (GREM1); the YWHAH binding site for Gremlin 1 was mapped to residues 61–80 of YWHAH, and the Gremlin 1 binding site for YWHAH was mapped to residues 1–67 of Gremlin 1.","method":"Yeast two-hybrid screen, GST pull-down assay, and co-immunoprecipitation","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown with domain mapping, single lab","pmids":["16545136"],"is_preprint":false},{"year":2013,"finding":"14-3-3η (YWHAH) accumulates at meiotic spindles (both meiosis I and II) in mouse oocytes and directly interacts with α-tubulin at the metaphase II spindle. Morpholino-mediated knockdown of 14-3-3η caused deformed or absent meiotic spindles, chromosome clumping, and failure of polar body formation in 76% of injected oocytes, establishing a required role in meiotic spindle assembly.","method":"In situ proximity ligation assay (protein-protein interaction), immunofluorescence, microinjection of translation-blocking morpholino oligonucleotide (loss-of-function)","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (PLA, immunofluorescence, morpholino KD with specific phenotypic readout) in a single rigorous study with appropriate controls","pmids":["23547714"],"is_preprint":false},{"year":2016,"finding":"Loss of Ywhah in mice causes deafness and degeneration of cochlear outer hair cells. In vitro, disease-associated YWHAH variants show reduced capacity to bind the pro-apoptotic protein Bad and induce mitochondrial fragmentation and increased susceptibility to apoptosis, indicating that YWHAH normally suppresses apoptosis in hair cells through Bad binding.","method":"Ywhah knockout mouse model (auditory phenotype), in vitro variant functional assays (mitochondrial morphology, apoptosis assays, Bad binding)","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined phenotype plus in vitro mechanistic validation of Bad binding and apoptotic susceptibility, multiple orthogonal methods","pmids":["27275396"],"is_preprint":false},{"year":2023,"finding":"YWHAH interacts with the transcription factor Fra-1 in gastric cancer cells; YWHAH positively regulates Fra-1 mRNA and protein expression, and through Fra-1, activates the HMGA1/PI3K/AKT/mTOR signaling pathway to promote gastric cancer cell proliferation.","method":"Co-immunoprecipitation combined with LC-MS/MS (interaction identification), Western blot, flow cytometry, whole proteome analysis, knockdown/overexpression functional assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for interaction discovery plus functional epistasis via Western blot and pathway analysis, single lab","pmids":["37415737"],"is_preprint":false},{"year":2024,"finding":"GREM1 binds YWHAH in dental pulp stem cells (DPSCs) and negatively regulates their osteo-/dentinogenic differentiation. Knockdown of YWHAH suppressed, while overexpression of YWHAH promoted, osteo-/dentinogenesis in vitro and in vivo, placing YWHAH downstream of GREM1 in this differentiation pathway.","method":"Co-immunoprecipitation, polypeptide microarray (binding site identification), siRNA knockdown, overexpression, ALP activity, alizarin red staining, in vivo nude mouse assay","journal":"The Chinese journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional KD/OE and in vivo validation, single lab","pmids":["39221981"],"is_preprint":false},{"year":2024,"finding":"METTL14-mediated m6A methylation of YWHAH transcripts (particularly in the 5' UTR) is recognized by the m6A reader YTHDF1, leading to degradation of YWHAH mRNA. Downregulation of YWHAH expression activates the PI3K/AKT signaling pathway and promotes neuroblastoma cell activity.","method":"MeRIP-seq, RNA-seq, METTL14 knockdown in NB cells (in vitro and nude mouse xenograft), PI3K/AKT pathway Western blot","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq identifies m6A sites on YWHAH, functional KD confirms pathway activation, single lab with multiple methods","pmids":["38649363"],"is_preprint":false},{"year":2020,"finding":"miR-660-5p directly targets YWHAH (validated by dual luciferase reporter assay); knockdown of YWHAH partially reverses the tumor-suppressive effects of miR-660-5p inhibitor. The miR-660-5p/YWHAH axis activates the PI3K/AKT pathway, promoting EMT and cell cycle progression in hepatocellular carcinoma cells.","method":"Dual luciferase reporter assay, YWHAH knockdown, PI3K/AKT pathway analysis, in vitro and in vivo HCC models","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miRNA-target interaction, functional rescue experiment, single lab","pmids":["32807493"],"is_preprint":false},{"year":2025,"finding":"YWHAH negatively regulates the MAPK/ERK signaling pathway (reducing phospho-ERK1/2 and phospho-ELK-1) to suppress autophagy in colorectal cancer cells. YWHAH knockdown enhanced autophagy (increased ATG7, LC3II/I; decreased p62) and inhibited CRC cell migration and invasion, while YWHAH overexpression had opposite effects; the ERK inhibitor PD98059 reversed autophagy activation by YWHAH knockdown.","method":"YWHAH knockdown and overexpression, autophagy flux assays (LC3II/I, p62, ATG7), ERK pathway inhibitor/agonist pharmacological rescue, nude mouse xenograft","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue experiments validate MAPK/ERK pathway mechanism, supported by in vivo xenograft, single lab","pmids":["41133478"],"is_preprint":false},{"year":2025,"finding":"Ywhah exhibits strong binding affinity to cytoskeletal proteins in brown adipocytes, as determined by affinity purification-mass spectrometry, and its expression is highly correlated with cytoskeletal gene set variation analysis (GSVA) scores, suggesting a role in cytoskeletal regulation downstream of the ADRβ3-COX2 signaling axis.","method":"Affinity purification-mass spectrometry, RNA sequencing, WGCNA, machine learning feature importance analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single affinity purification/MS experiment without functional validation of the cytoskeletal interaction, single lab","pmids":["40243609"],"is_preprint":false},{"year":1996,"finding":"The human YWHAH gene structure was determined: it comprises two exons separated by one intron (~8 kb), spans ~10 kb, and was chromosomally mapped to 22q12.1–q13.1 by FISH.","method":"S1 nuclease mapping, primer extension, RACE, FISH","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple direct molecular methods for gene structure determination and chromosomal localization, foundational characterization paper","pmids":["8812417"],"is_preprint":false}],"current_model":"YWHAH encodes 14-3-3η, a phosphoserine/phosphothreonine-binding adaptor protein that localizes to meiotic spindles (where it interacts with α-tubulin to support spindle assembly), binds the pro-apoptotic protein Bad to suppress apoptosis in cochlear hair cells, interacts with binding partners including Gremlin 1 (GREM1) and the transcription factor Fra-1 to modulate PI3K/AKT/mTOR signaling, negatively regulates the MAPK/ERK pathway to suppress autophagy in cancer cells, and is post-transcriptionally regulated by m6A methylation via METTL14/YTHDF1-mediated mRNA degradation."},"narrative":{"mechanistic_narrative":"YWHAH encodes 14-3-3η, a phosphopeptide-binding adaptor that links cytoskeletal organization, apoptotic control, and growth-factor signaling across multiple cell types [PMID:23547714, PMID:27275396, PMID:37415737]. In dividing germ cells it accumulates on meiotic spindles and binds α-tubulin, and its loss produces deformed or absent spindles, chromosome clumping, and failed polar body formation, establishing a required role in meiotic spindle assembly [PMID:23547714]. In cochlear outer hair cells YWHAH suppresses apoptosis by binding the pro-apoptotic protein Bad; disease-associated variants that bind Bad poorly drive mitochondrial fragmentation and apoptotic susceptibility, and loss of Ywhah in mice causes deafness with outer hair cell degeneration [PMID:27275396]. YWHAH also operates as a physical hub for partners including Gremlin 1 (GREM1), with reciprocal binding sites mapped to YWHAH residues 61–80 and GREM1 residues 1–67, a complex that negatively regulates osteo-/dentinogenic differentiation of dental pulp stem cells [PMID:16545136, PMID:39221981]. In cancer cells YWHAH modulates two signaling axes in opposing directions: it interacts with and elevates the transcription factor Fra-1 to activate HMGA1/PI3K/AKT/mTOR signaling and proliferation [PMID:37415737], and it negatively regulates MAPK/ERK signaling to suppress autophagy, migration, and invasion [PMID:41133478]. YWHAH expression is itself controlled post-transcriptionally—by miR-660-5p targeting and by METTL14-deposited m6A marks read by YTHDF1 that promote mRNA degradation—with reduced YWHAH activating PI3K/AKT signaling [PMID:38649363, PMID:32807493].","teleology":[{"year":1996,"claim":"Established the basic genomic architecture of the gene, providing the foundation for all subsequent functional study of the 14-3-3η isoform.","evidence":"S1 nuclease mapping, primer extension, RACE, and FISH defining a two-exon gene at 22q12.1–q13.1","pmids":["8812417"],"confidence":"High","gaps":["No functional or protein-level activity addressed","No regulatory element characterization"]},{"year":2006,"claim":"Identified GREM1 as a physical partner and mapped reciprocal binding interfaces, defining YWHAH as a docking adaptor for a secreted BMP antagonist.","evidence":"Yeast two-hybrid, GST pull-down, and Co-IP with domain mapping","pmids":["16545136"],"confidence":"Medium","gaps":["Functional consequence of the interaction not established in this study","Single lab; no in vivo context"]},{"year":2013,"claim":"Demonstrated a required structural role in meiotic spindle assembly through direct α-tubulin engagement, moving YWHAH from adaptor to cytoskeletal regulator.","evidence":"In situ PLA, immunofluorescence, and translation-blocking morpholino knockdown in mouse oocytes","pmids":["23547714"],"confidence":"High","gaps":["Phosphopeptide-dependence of α-tubulin binding not resolved","Mechanism linking spindle binding to chromosome alignment unclear"]},{"year":2016,"claim":"Defined an anti-apoptotic function via Bad binding and tied it to a deafness phenotype, connecting molecular binding capacity to organ-level pathology.","evidence":"Ywhah knockout mouse auditory phenotyping plus in vitro variant assays of Bad binding, mitochondrial morphology, and apoptosis","pmids":["27275396"],"confidence":"High","gaps":["Whether Bad sequestration is the sole protective mechanism in hair cells unknown","Variant-to-human-disease causality not formally genetic here"]},{"year":2020,"claim":"Showed YWHAH is a direct miRNA target whose suppression drives PI3K/AKT-dependent tumor phenotypes, identifying post-transcriptional control as a node in oncogenic signaling.","evidence":"Dual luciferase reporter, YWHAH knockdown rescue, and PI3K/AKT analysis in HCC models","pmids":["32807493"],"confidence":"Medium","gaps":["Direct molecular link between YWHAH and PI3K/AKT components not defined","Single-lab cancer model"]},{"year":2023,"claim":"Placed YWHAH upstream of a Fra-1/HMGA1/PI3K/AKT/mTOR proliferative axis, showing it can positively regulate a transcription factor partner's expression.","evidence":"Co-IP/LC-MS/MS interaction discovery with knockdown/overexpression epistasis in gastric cancer cells","pmids":["37415737"],"confidence":"Medium","gaps":["Mechanism by which YWHAH raises Fra-1 mRNA unclear","Direct vs indirect pathway activation not separated"]},{"year":2024,"claim":"Resolved m6A as a layer controlling YWHAH abundance, linking epitranscriptomic regulation to PI3K/AKT activation in neuroblastoma.","evidence":"MeRIP-seq, METTL14 knockdown, and PI3K/AKT Western blot in NB cells and xenografts","pmids":["38649363"],"confidence":"Medium","gaps":["Direct YTHDF1–YWHAH transcript binding shown only at population level","How reduced YWHAH protein activates PI3K/AKT not mechanistically defined"]},{"year":2024,"claim":"Extended the GREM1–YWHAH partnership to a developmental differentiation program, showing YWHAH acts downstream of GREM1 to control osteo-/dentinogenesis.","evidence":"Co-IP, polypeptide microarray binding mapping, siRNA/overexpression, and in vivo nude mouse assays in DPSCs","pmids":["39221981"],"confidence":"Medium","gaps":["Downstream effectors of YWHAH in differentiation undefined","Relationship to its cancer signaling roles unclear"]},{"year":2025,"claim":"Identified a MAPK/ERK-suppressing, autophagy-inhibiting role, demonstrating that YWHAH can negatively regulate a kinase pathway in contrast to its positive PI3K/AKT effects.","evidence":"Knockdown/overexpression with autophagy flux assays and ERK inhibitor/agonist pharmacological rescue plus xenograft in CRC cells","pmids":["41133478"],"confidence":"Medium","gaps":["Direct YWHAH target within the ERK cascade not identified","Reconciliation with PI3K/AKT-promoting findings unaddressed"]},{"year":2025,"claim":"Provided proteomic evidence for broad cytoskeletal protein association in adipocytes, hinting at a conserved cytoskeletal-regulatory theme beyond the meiotic spindle.","evidence":"Affinity purification-mass spectrometry, RNA-seq, WGCNA, and machine learning in brown adipocytes","pmids":["40243609"],"confidence":"Low","gaps":["Single affinity-MS experiment without functional validation of cytoskeletal interactions","No specific binding partner confirmed orthogonally"]},{"year":null,"claim":"How YWHAH's opposing effects on PI3K/AKT (promoting) and MAPK/ERK (suppressing) signaling are coordinated within a single cell, and which phosphorylated client proteins mediate each output, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified client map linking 14-3-3η binding to each downstream pathway","Context-dependence across tissues not mechanistically explained","Structural basis of phosphopeptide recognition for these clients not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":[],"partners":["GREM1","TUBA (ALPHA-TUBULIN)","BAD","FOSL1 (FRA-1)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04917","full_name":"14-3-3 protein eta","aliases":["Protein AS1"],"length_aa":246,"mass_kda":28.2,"function":"Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q04917/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YWHAH","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000128245","cell_line_id":"CID000465","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"cytoplasmic","grade":3},{"compartment":"cell_contact","grade":2}],"interactors":[{"gene":"ARL6IP5","stoichiometry":10.0},{"gene":"ARL8B","stoichiometry":10.0},{"gene":"KRAS","stoichiometry":10.0},{"gene":"YWHAE","stoichiometry":10.0},{"gene":"ACTR2","stoichiometry":4.0},{"gene":"ARL1","stoichiometry":4.0},{"gene":"ARL2","stoichiometry":4.0},{"gene":"ARL3","stoichiometry":4.0},{"gene":"NCKAP1","stoichiometry":4.0},{"gene":"TRAPPC1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000465","total_profiled":1310},"omim":[{"mim_id":"614191","title":"DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5","url":"https://www.omim.org/entry/614191"},{"mim_id":"611448","title":"BMS1 RIBOSOME BIOGENESIS FACTOR; BMS1","url":"https://www.omim.org/entry/611448"},{"mim_id":"610679","title":"CYCLIN-DEPENDENT KINASE 14; CDK14","url":"https://www.omim.org/entry/610679"},{"mim_id":"610221","title":"AKT1 SUBSTRATE 1, PROLINE-RICH; AKT1S1","url":"https://www.omim.org/entry/610221"},{"mim_id":"607757","title":"CHIBBY FAMILY, MEMBER 1, BETA-CATENIN ANTAGONIST; CBY1","url":"https://www.omim.org/entry/607757"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli rim","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":288.0},{"tissue":"brain","ntpm":728.3}],"url":"https://www.proteinatlas.org/search/YWHAH"},"hgnc":{"alias_symbol":[],"prev_symbol":["YWHA1"]},"alphafold":{"accession":"Q04917","domains":[{"cath_id":"1.20.190.20","chopping":"1-111","consensus_level":"medium","plddt":96.7293,"start":1,"end":111},{"cath_id":"1.20.190.20","chopping":"113-239","consensus_level":"medium","plddt":95.8891,"start":113,"end":239}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04917","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04917-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04917-F1-predicted_aligned_error_v6.png","plddt_mean":95.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YWHAH","jax_strain_url":"https://www.jax.org/strain/search?query=YWHAH"},"sequence":{"accession":"Q04917","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04917.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04917/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04917"}},"corpus_meta":[{"pmid":"16545136","id":"PMC_16545136","title":"The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein.","date":"2006","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16545136","citation_count":95,"is_preprint":false},{"pmid":"10206237","id":"PMC_10206237","title":"14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10206237","citation_count":58,"is_preprint":false},{"pmid":"19160447","id":"PMC_19160447","title":"Family-based association of YWHAH in psychotic bipolar disorder.","date":"2009","source":"American journal of medical genetics. 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AD","date":"2024-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.14.613003","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17504,"output_tokens":2571,"usd":0.045539,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9813,"output_tokens":3480,"usd":0.068032,"stage2_stop_reason":"end_turn"},"total_usd":0.113571,"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\": 2006,\n      \"finding\": \"YWHAH (14-3-3 eta) physically interacts with Gremlin 1 (GREM1); the YWHAH binding site for Gremlin 1 was mapped to residues 61–80 of YWHAH, and the Gremlin 1 binding site for YWHAH was mapped to residues 1–67 of Gremlin 1.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down assay, and co-immunoprecipitation\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown with domain mapping, single lab\",\n      \"pmids\": [\"16545136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"14-3-3η (YWHAH) accumulates at meiotic spindles (both meiosis I and II) in mouse oocytes and directly interacts with α-tubulin at the metaphase II spindle. Morpholino-mediated knockdown of 14-3-3η caused deformed or absent meiotic spindles, chromosome clumping, and failure of polar body formation in 76% of injected oocytes, establishing a required role in meiotic spindle assembly.\",\n      \"method\": \"In situ proximity ligation assay (protein-protein interaction), immunofluorescence, microinjection of translation-blocking morpholino oligonucleotide (loss-of-function)\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (PLA, immunofluorescence, morpholino KD with specific phenotypic readout) in a single rigorous study with appropriate controls\",\n      \"pmids\": [\"23547714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Ywhah in mice causes deafness and degeneration of cochlear outer hair cells. In vitro, disease-associated YWHAH variants show reduced capacity to bind the pro-apoptotic protein Bad and induce mitochondrial fragmentation and increased susceptibility to apoptosis, indicating that YWHAH normally suppresses apoptosis in hair cells through Bad binding.\",\n      \"method\": \"Ywhah knockout mouse model (auditory phenotype), in vitro variant functional assays (mitochondrial morphology, apoptosis assays, Bad binding)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined phenotype plus in vitro mechanistic validation of Bad binding and apoptotic susceptibility, multiple orthogonal methods\",\n      \"pmids\": [\"27275396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YWHAH interacts with the transcription factor Fra-1 in gastric cancer cells; YWHAH positively regulates Fra-1 mRNA and protein expression, and through Fra-1, activates the HMGA1/PI3K/AKT/mTOR signaling pathway to promote gastric cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation combined with LC-MS/MS (interaction identification), Western blot, flow cytometry, whole proteome analysis, knockdown/overexpression functional assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for interaction discovery plus functional epistasis via Western blot and pathway analysis, single lab\",\n      \"pmids\": [\"37415737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GREM1 binds YWHAH in dental pulp stem cells (DPSCs) and negatively regulates their osteo-/dentinogenic differentiation. Knockdown of YWHAH suppressed, while overexpression of YWHAH promoted, osteo-/dentinogenesis in vitro and in vivo, placing YWHAH downstream of GREM1 in this differentiation pathway.\",\n      \"method\": \"Co-immunoprecipitation, polypeptide microarray (binding site identification), siRNA knockdown, overexpression, ALP activity, alizarin red staining, in vivo nude mouse assay\",\n      \"journal\": \"The Chinese journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional KD/OE and in vivo validation, single lab\",\n      \"pmids\": [\"39221981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14-mediated m6A methylation of YWHAH transcripts (particularly in the 5' UTR) is recognized by the m6A reader YTHDF1, leading to degradation of YWHAH mRNA. Downregulation of YWHAH expression activates the PI3K/AKT signaling pathway and promotes neuroblastoma cell activity.\",\n      \"method\": \"MeRIP-seq, RNA-seq, METTL14 knockdown in NB cells (in vitro and nude mouse xenograft), PI3K/AKT pathway Western blot\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq identifies m6A sites on YWHAH, functional KD confirms pathway activation, single lab with multiple methods\",\n      \"pmids\": [\"38649363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-660-5p directly targets YWHAH (validated by dual luciferase reporter assay); knockdown of YWHAH partially reverses the tumor-suppressive effects of miR-660-5p inhibitor. The miR-660-5p/YWHAH axis activates the PI3K/AKT pathway, promoting EMT and cell cycle progression in hepatocellular carcinoma cells.\",\n      \"method\": \"Dual luciferase reporter assay, YWHAH knockdown, PI3K/AKT pathway analysis, in vitro and in vivo HCC models\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miRNA-target interaction, functional rescue experiment, single lab\",\n      \"pmids\": [\"32807493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YWHAH negatively regulates the MAPK/ERK signaling pathway (reducing phospho-ERK1/2 and phospho-ELK-1) to suppress autophagy in colorectal cancer cells. YWHAH knockdown enhanced autophagy (increased ATG7, LC3II/I; decreased p62) and inhibited CRC cell migration and invasion, while YWHAH overexpression had opposite effects; the ERK inhibitor PD98059 reversed autophagy activation by YWHAH knockdown.\",\n      \"method\": \"YWHAH knockdown and overexpression, autophagy flux assays (LC3II/I, p62, ATG7), ERK pathway inhibitor/agonist pharmacological rescue, nude mouse xenograft\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue experiments validate MAPK/ERK pathway mechanism, supported by in vivo xenograft, single lab\",\n      \"pmids\": [\"41133478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ywhah exhibits strong binding affinity to cytoskeletal proteins in brown adipocytes, as determined by affinity purification-mass spectrometry, and its expression is highly correlated with cytoskeletal gene set variation analysis (GSVA) scores, suggesting a role in cytoskeletal regulation downstream of the ADRβ3-COX2 signaling axis.\",\n      \"method\": \"Affinity purification-mass spectrometry, RNA sequencing, WGCNA, machine learning feature importance analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single affinity purification/MS experiment without functional validation of the cytoskeletal interaction, single lab\",\n      \"pmids\": [\"40243609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human YWHAH gene structure was determined: it comprises two exons separated by one intron (~8 kb), spans ~10 kb, and was chromosomally mapped to 22q12.1–q13.1 by FISH.\",\n      \"method\": \"S1 nuclease mapping, primer extension, RACE, FISH\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple direct molecular methods for gene structure determination and chromosomal localization, foundational characterization paper\",\n      \"pmids\": [\"8812417\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YWHAH encodes 14-3-3η, a phosphoserine/phosphothreonine-binding adaptor protein that localizes to meiotic spindles (where it interacts with α-tubulin to support spindle assembly), binds the pro-apoptotic protein Bad to suppress apoptosis in cochlear hair cells, interacts with binding partners including Gremlin 1 (GREM1) and the transcription factor Fra-1 to modulate PI3K/AKT/mTOR signaling, negatively regulates the MAPK/ERK pathway to suppress autophagy in cancer cells, and is post-transcriptionally regulated by m6A methylation via METTL14/YTHDF1-mediated mRNA degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YWHAH encodes 14-3-3\\u03b7, a phosphopeptide-binding adaptor that links cytoskeletal organization, apoptotic control, and growth-factor signaling across multiple cell types [#1, #2, #3]. In dividing germ cells it accumulates on meiotic spindles and binds \\u03b1-tubulin, and its loss produces deformed or absent spindles, chromosome clumping, and failed polar body formation, establishing a required role in meiotic spindle assembly [#1]. In cochlear outer hair cells YWHAH suppresses apoptosis by binding the pro-apoptotic protein Bad; disease-associated variants that bind Bad poorly drive mitochondrial fragmentation and apoptotic susceptibility, and loss of Ywhah in mice causes deafness with outer hair cell degeneration [#2]. YWHAH also operates as a physical hub for partners including Gremlin 1 (GREM1), with reciprocal binding sites mapped to YWHAH residues 61\\u201380 and GREM1 residues 1\\u201367, a complex that negatively regulates osteo-/dentinogenic differentiation of dental pulp stem cells [#0, #4]. In cancer cells YWHAH modulates two signaling axes in opposing directions: it interacts with and elevates the transcription factor Fra-1 to activate HMGA1/PI3K/AKT/mTOR signaling and proliferation [#3], and it negatively regulates MAPK/ERK signaling to suppress autophagy, migration, and invasion [#7]. YWHAH expression is itself controlled post-transcriptionally\\u2014by miR-660-5p targeting and by METTL14-deposited m6A marks read by YTHDF1 that promote mRNA degradation\\u2014with reduced YWHAH activating PI3K/AKT signaling [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the basic genomic architecture of the gene, providing the foundation for all subsequent functional study of the 14-3-3\\u03b7 isoform.\",\n      \"evidence\": \"S1 nuclease mapping, primer extension, RACE, and FISH defining a two-exon gene at 22q12.1\\u2013q13.1\",\n      \"pmids\": [\"8812417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional or protein-level activity addressed\", \"No regulatory element characterization\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified GREM1 as a physical partner and mapped reciprocal binding interfaces, defining YWHAH as a docking adaptor for a secreted BMP antagonist.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and Co-IP with domain mapping\",\n      \"pmids\": [\"16545136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the interaction not established in this study\", \"Single lab; no in vivo context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a required structural role in meiotic spindle assembly through direct \\u03b1-tubulin engagement, moving YWHAH from adaptor to cytoskeletal regulator.\",\n      \"evidence\": \"In situ PLA, immunofluorescence, and translation-blocking morpholino knockdown in mouse oocytes\",\n      \"pmids\": [\"23547714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphopeptide-dependence of \\u03b1-tubulin binding not resolved\", \"Mechanism linking spindle binding to chromosome alignment unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined an anti-apoptotic function via Bad binding and tied it to a deafness phenotype, connecting molecular binding capacity to organ-level pathology.\",\n      \"evidence\": \"Ywhah knockout mouse auditory phenotyping plus in vitro variant assays of Bad binding, mitochondrial morphology, and apoptosis\",\n      \"pmids\": [\"27275396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Bad sequestration is the sole protective mechanism in hair cells unknown\", \"Variant-to-human-disease causality not formally genetic here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed YWHAH is a direct miRNA target whose suppression drives PI3K/AKT-dependent tumor phenotypes, identifying post-transcriptional control as a node in oncogenic signaling.\",\n      \"evidence\": \"Dual luciferase reporter, YWHAH knockdown rescue, and PI3K/AKT analysis in HCC models\",\n      \"pmids\": [\"32807493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between YWHAH and PI3K/AKT components not defined\", \"Single-lab cancer model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed YWHAH upstream of a Fra-1/HMGA1/PI3K/AKT/mTOR proliferative axis, showing it can positively regulate a transcription factor partner's expression.\",\n      \"evidence\": \"Co-IP/LC-MS/MS interaction discovery with knockdown/overexpression epistasis in gastric cancer cells\",\n      \"pmids\": [\"37415737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which YWHAH raises Fra-1 mRNA unclear\", \"Direct vs indirect pathway activation not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved m6A as a layer controlling YWHAH abundance, linking epitranscriptomic regulation to PI3K/AKT activation in neuroblastoma.\",\n      \"evidence\": \"MeRIP-seq, METTL14 knockdown, and PI3K/AKT Western blot in NB cells and xenografts\",\n      \"pmids\": [\"38649363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct YTHDF1\\u2013YWHAH transcript binding shown only at population level\", \"How reduced YWHAH protein activates PI3K/AKT not mechanistically defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the GREM1\\u2013YWHAH partnership to a developmental differentiation program, showing YWHAH acts downstream of GREM1 to control osteo-/dentinogenesis.\",\n      \"evidence\": \"Co-IP, polypeptide microarray binding mapping, siRNA/overexpression, and in vivo nude mouse assays in DPSCs\",\n      \"pmids\": [\"39221981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of YWHAH in differentiation undefined\", \"Relationship to its cancer signaling roles unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a MAPK/ERK-suppressing, autophagy-inhibiting role, demonstrating that YWHAH can negatively regulate a kinase pathway in contrast to its positive PI3K/AKT effects.\",\n      \"evidence\": \"Knockdown/overexpression with autophagy flux assays and ERK inhibitor/agonist pharmacological rescue plus xenograft in CRC cells\",\n      \"pmids\": [\"41133478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct YWHAH target within the ERK cascade not identified\", \"Reconciliation with PI3K/AKT-promoting findings unaddressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided proteomic evidence for broad cytoskeletal protein association in adipocytes, hinting at a conserved cytoskeletal-regulatory theme beyond the meiotic spindle.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, RNA-seq, WGCNA, and machine learning in brown adipocytes\",\n      \"pmids\": [\"40243609\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single affinity-MS experiment without functional validation of cytoskeletal interactions\", \"No specific binding partner confirmed orthogonally\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How YWHAH's opposing effects on PI3K/AKT (promoting) and MAPK/ERK (suppressing) signaling are coordinated within a single cell, and which phosphorylated client proteins mediate each output, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified client map linking 14-3-3\\u03b7 binding to each downstream pathway\", \"Context-dependence across tissues not mechanistically explained\", \"Structural basis of phosphopeptide recognition for these clients not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GREM1\", \"TUBA (alpha-tubulin)\", \"BAD\", \"FOSL1 (Fra-1)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}