Affinage

YWHAH

14-3-3 protein eta · UniProt Q04917

Length
246 aa
Mass
28.2 kDa
Annotated
2026-06-11
27 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 High

    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

    PMID:8812417

    Open questions at the time
    • No functional or protein-level activity addressed
    • No regulatory element characterization
  2. 2006 Medium

    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

    PMID:16545136

    Open questions at the time
    • Functional consequence of the interaction not established in this study
    • Single lab; no in vivo context
  3. 2013 High

    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

    PMID:23547714

    Open questions at the time
    • Phosphopeptide-dependence of α-tubulin binding not resolved
    • Mechanism linking spindle binding to chromosome alignment unclear
  4. 2016 High

    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

    PMID:27275396

    Open questions at the time
    • Whether Bad sequestration is the sole protective mechanism in hair cells unknown
    • Variant-to-human-disease causality not formally genetic here
  5. 2020 Medium

    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

    PMID:32807493

    Open questions at the time
    • Direct molecular link between YWHAH and PI3K/AKT components not defined
    • Single-lab cancer model
  6. 2023 Medium

    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

    PMID:37415737

    Open questions at the time
    • Mechanism by which YWHAH raises Fra-1 mRNA unclear
    • Direct vs indirect pathway activation not separated
  7. 2024 Medium

    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

    PMID:38649363

    Open questions at the time
    • Direct YTHDF1–YWHAH transcript binding shown only at population level
    • How reduced YWHAH protein activates PI3K/AKT not mechanistically defined
  8. 2024 Medium

    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

    PMID:39221981

    Open questions at the time
    • Downstream effectors of YWHAH in differentiation undefined
    • Relationship to its cancer signaling roles unclear
  9. 2025 Medium

    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

    PMID:41133478

    Open questions at the time
    • Direct YWHAH target within the ERK cascade not identified
    • Reconciliation with PI3K/AKT-promoting findings unaddressed
  10. 2025 Low

    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

    PMID:40243609

    Open questions at the time
    • Single affinity-MS experiment without functional validation of cytoskeletal interactions
    • No specific binding partner confirmed orthogonally

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BADFOSL1 (FRA-1)GREM1TUBA (ALPHA-TUBULIN)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Yeast two-hybrid screen, GST pull-down assay, and co-immunoprecipitation BMC cancer Medium 16545136
2013 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. In situ proximity ligation assay (protein-protein interaction), immunofluorescence, microinjection of translation-blocking morpholino oligonucleotide (loss-of-function) BMC developmental biology High 23547714
2016 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. Ywhah knockout mouse model (auditory phenotype), in vitro variant functional assays (mitochondrial morphology, apoptosis assays, Bad binding) Cell death discovery High 27275396
2023 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. Co-immunoprecipitation combined with LC-MS/MS (interaction identification), Western blot, flow cytometry, whole proteome analysis, knockdown/overexpression functional assays Oncology research Medium 37415737
2024 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. Co-immunoprecipitation, polypeptide microarray (binding site identification), siRNA knockdown, overexpression, ALP activity, alizarin red staining, in vivo nude mouse assay The Chinese journal of dental research Medium 39221981
2024 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. MeRIP-seq, RNA-seq, METTL14 knockdown in NB cells (in vitro and nude mouse xenograft), PI3K/AKT pathway Western blot Cell death discovery Medium 38649363
2020 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. Dual luciferase reporter assay, YWHAH knockdown, PI3K/AKT pathway analysis, in vitro and in vivo HCC models Biochemical and biophysical research communications Medium 32807493
2025 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. YWHAH knockdown and overexpression, autophagy flux assays (LC3II/I, p62, ATG7), ERK pathway inhibitor/agonist pharmacological rescue, nude mouse xenograft International journal of molecular medicine Medium 41133478
2025 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. Affinity purification-mass spectrometry, RNA sequencing, WGCNA, machine learning feature importance analysis International journal of molecular sciences Low 40243609
1996 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. S1 nuclease mapping, primer extension, RACE, FISH Genomics High 8812417

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC cancer 95 16545136
1999 14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia. American journal of medical genetics 58 10206237
2009 Family-based association of YWHAH in psychotic bipolar disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 44 19160447
1996 Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH). Genomics 40 8812417
2020 MiR-660-5p promotes the progression of hepatocellular carcinoma by interaction with YWHAH via PI3K/Akt signaling pathway. Biochemical and biophysical research communications 25 32807493
2020 IncRNA MAPKAPK5-AS1 promotes proliferation and migration of thyroid cancer cell lines by targeting miR-519e-5p/YWHAH. European journal of histochemistry : EJH 25 33272009
2013 Evidence for the requirement of 14-3-3eta (YWHAH) in meiotic spindle assembly during mouse oocyte maturation. BMC developmental biology 21 23547714
2023 YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells. Oncology research 13 37415737
2020 Significant reductions in apoptosis-related proteins (HSPA6, HSPA8, ITGB3, YWHAH, and PRDX6) are involved in immune thrombocytopenia. Journal of thrombosis and thrombolysis 13 33047245
2016 Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration. Cell death discovery 12 27275396
2024 Unveiling YWHAH: A potential therapeutic target for overcoming CD8+ T cell exhaustion in colorectal cancer. International immunopharmacology 11 38796965
2022 Circ_0000144 acts as a miR-1178-3p decoy to promote cell malignancy and angiogenesis by increasing YWHAH expression in papillary thyroid cancer. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 11 35902926
2024 METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism. Cell death discovery 10 38649363
2023 Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development. Cells 9 36980307
2005 [Association study between NPY and YWHAH gene polymorphisms and schizophrenia]. Yi chuan xue bao = Acta genetica Sinica 8 16459651
2023 LINC00943 regulates miR-1252-5p/YWHAH axis to promote tumor proliferation and metastasis in lung adenocarcinoma. Heliyon 7 37332930
2022 YWHAH Genetic Variants are Associated with Increased Hypoxia Inducible Factor-1α/Vascular Endothelial Growth Factor in Egyptian Rheumatoid Arthritis Patients. Biochemical genetics 4 35190930
2011 A polymorphism in the YWHAH gene encoding 14-3-3 eta that is not associated with sporadic Creutzfeldt-Jakob disease (CJD). Molecular biology reports 4 21739144
2025 Anti-cancer effect of midazolam via downregulating YWHAH in papillary thyroid cancer cells. Discover oncology 2 39836297
2023 YWHAH, a member of 14-3-3 family proteins, and PSME2, the proteasome activator subunit 2, are key host factors of Japanese encephalitis virus infection. BMC medical genomics 2 37430323
2023 Inhibiting miR-33b-5p Enhances Chemoresistance in Lung Adenocarcinoma by Targeting YWHAH to Regulate Epithelial-mesenchymal Transition. Anticancer research 2 38030169
2025 LncRNA-GPHN Regulates Epilepsy by Inhibiting Apoptosis via the miR-320/YWHAH Axis in an Immature Rat Model of Status Epilepticus. Journal of cellular and molecular medicine 1 40346986
2025 YWHAH‑driven autophagy via MAPK/ERK signaling enhances CRC cell migration and invasion. International journal of molecular medicine 1 41133478
2026 METTL14 modulates the nasopharyngeal carcinoma microenvironment via m6A-modified YWHAH identified through single-cell and machine learning analyses. Frontiers in immunology 0 41705255
2025 Exercise Improves the Cytoskeletal and Metabolic Functions of Brown Adipocytes Through the ADRβ3/COX2-Ywhah Axis. International journal of molecular sciences 0 40243609
2025 Synergistic epigenetic modulation by 5-aza-2'-deoxycytidine and Wnt3a drives osteogenic trans-differentiation of 3T3-L1 pre-adipocytes through Ywhah and Ywhae. Epigenomics 0 40792537
2024 GREM1 Negatively Regulates Osteo-/Dentinogenic Differentiation of Dental Pulp Stem Cells via Association with YWHAH. The Chinese journal of dental research 0 39221981

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