Affinage

YWHAH

14-3-3 protein eta · UniProt Q04917

Round 2 corrected
Length
246 aa
Mass
28.2 kDa
Annotated
2026-04-28
57 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YWHAH (14-3-3η) is a phosphoserine/phosphothreonine-binding scaffold protein that regulates cell survival, differentiation, and signaling across diverse tissues. It directly interacts with α-tubulin at meiotic spindles and is required for normal spindle assembly and polar body extrusion in mouse oocytes (PMID:23547714). YWHAH promotes cochlear hair cell survival by binding the pro-apoptotic protein Bad, and loss of Ywhah in mice causes deafness with outer hair cell degeneration (PMID:27275396). In cancer contexts, YWHAH modulates the PI3K/AKT and MAPK/ERK pathways—interacting with Fra-1 to activate HMGA1/PI3K/AKT/mTOR signaling in gastric cancer and negatively regulating ERK-mediated autophagy in colorectal cancer (PMID:37415737, PMID:41133478).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Structural characterization of the YWHAH gene established its two-exon architecture, transcription start site, and chromosomal location at 22q12.1–q13.1, providing the foundation for all subsequent functional studies.

    Evidence S1 nuclease mapping, primer extension, RACE, and FISH on human genomic DNA

    PMID:8812417

    Open questions at the time
    • No protein-level functional data at this stage
    • Promoter regulatory elements identified but not functionally validated
  2. 2006 Medium

    Identification of GREM1 as a direct binding partner of YWHAH, with reciprocal binding sites mapped, revealed that 14-3-3η participates in BMP/differentiation-related signaling beyond canonical phosphopeptide clients.

    Evidence Yeast two-hybrid, GST pull-down, and co-immunoprecipitation with domain-mapping constructs

    PMID:16545136

    Open questions at the time
    • Functional consequence of GREM1–YWHAH interaction was not defined in this study
    • Whether binding is phosphoserine-dependent was not tested
  3. 2013 High

    Demonstration that YWHAH localizes to meiotic spindles, directly interacts with α-tubulin, and is essential for spindle integrity established a cytoskeletal scaffolding role in oocyte meiosis.

    Evidence In situ proximity ligation assay for α-tubulin interaction, morpholino knockdown in mouse oocytes with spindle/chromosome phenotyping

    PMID:23547714

    Open questions at the time
    • Whether YWHAH binds tubulin via a phosphoserine motif or a non-canonical mode is unknown
    • Relevance to mitotic spindles in somatic cells not tested
  4. 2016 High

    Loss-of-function studies in mice revealed that YWHAH is required for cochlear hair cell survival, acting through Bad binding to prevent mitochondrial fragmentation and apoptosis—the first in vivo phenotype linking YWHAH to a specific tissue pathology (deafness).

    Evidence Ywhah knockout mice with auditory testing, immunohistochemistry in cochlea, and in vitro apoptosis/mitochondrial morphology assays with pathogenic variants

    PMID:27275396

    Open questions at the time
    • Whether YWHAH variants cause human deafness has not been confirmed
    • Contribution of other 14-3-3 isoforms to hair cell survival not assessed
  5. 2020 Medium

    Identification of YWHAH as a direct target of miR-660-5p in hepatocellular carcinoma linked post-transcriptional regulation of YWHAH to PI3K/AKT pathway activation, EMT, and cell cycle control.

    Evidence Dual luciferase reporter assay for direct miRNA targeting, siRNA rescue experiments, in vitro and in vivo tumor assays

    PMID:32807493

    Open questions at the time
    • Whether YWHAH directly activates PI3K or acts through an intermediate client is unclear
    • Single lab; independent replication in additional HCC cohorts lacking
  6. 2023 Medium

    Discovery of a physical YWHAH–Fra-1 interaction in gastric cancer cells, with YWHAH promoting Fra-1 expression and downstream HMGA1/PI3K/AKT/mTOR signaling, expanded the oncogenic scaffold model to transcription factor stabilization.

    Evidence Co-immunoprecipitation/LC-MS/MS, whole-proteome analysis, siRNA knockdown with pathway readouts

    PMID:37415737

    Open questions at the time
    • Whether YWHAH binds a phosphorylated motif in Fra-1 is not shown
    • Mechanism by which YWHAH upregulates Fra-1 mRNA is unknown
  7. 2024 Medium

    Epitranscriptomic regulation of YWHAH was defined: METTL14-mediated m6A modification of the YWHAH 5ʹ UTR promotes YTHDF1-dependent mRNA degradation, revealing a layer of post-transcriptional control that modulates downstream PI3K/AKT signaling in neuroblastoma.

    Evidence MeRIP-seq, RNA-seq, METTL14 and YTHDF1 knockdown, in vitro and in vivo neuroblastoma models

    PMID:38649363

    Open questions at the time
    • Generalizability of m6A-mediated YWHAH regulation to non-cancer tissues not tested
    • Whether YTHDF1-mediated degradation is the sole m6A reader pathway for YWHAH is unclear
  8. 2024 Medium

    Functional follow-up of the GREM1–YWHAH interaction in dental pulp stem cells showed YWHAH promotes osteo-/dentinogenic differentiation while GREM1 antagonizes this effect, assigning a physiological differentiation role to the interaction first mapped in 2006.

    Evidence Co-immunoprecipitation, polypeptide microarray binding-site mapping, in vitro mineralization and in vivo nude mouse transplantation

    PMID:39221981

    Open questions at the time
    • Signaling pathway downstream of YWHAH in osteogenic differentiation not fully delineated
    • Whether GREM1 displaces other YWHAH clients or sequesters YWHAH is not resolved
  9. 2025 Medium

    YWHAH was placed upstream of ERK-mediated autophagy in colorectal cancer: YWHAH negatively regulates MAPK/ERK signaling to suppress autophagy, and pharmacological rescue experiments confirmed the causal pathway order.

    Evidence siRNA knockdown and overexpression, ERK inhibitor/agonist rescue, autophagy flux assays, xenograft mouse model

    PMID:41133478

    Open questions at the time
    • Direct YWHAH client responsible for ERK suppression not identified
    • Whether autophagy suppression is 14-3-3η-isoform-specific or shared among 14-3-3 family members is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how YWHAH selects among its diverse clients (Bad, α-tubulin, Fra-1, GREM1, Raf/ERK effectors) in different cellular contexts, and whether isoform-specific structural features dictate client preference over other 14-3-3 family members.
  • No structural model of YWHAH with any of its identified clients
  • Isoform-specific versus redundant roles not systematically tested
  • No unbiased phosphoproteomics-based client map for 14-3-3η

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
BADFOSL1GREM1TUBA1AYTHDF1

Evidence

Reading pass · 11 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, as demonstrated by yeast two-hybrid screen, GST pull-down, and co-immunoprecipitation. Yeast two-hybrid, GST pull-down, co-immunoprecipitation BMC cancer Medium 16545136
1996 The human YWHAH gene was structurally characterized: it is composed of two exons separated by one long intron (~8 kb) spanning ~10 kb, with a defined transcription initiation site and multiple regulatory elements in the 5'-flanking region (GC boxes, CAAT box-like sequences, CRE, AP-2, E boxes, etc.), and was chromosomally mapped to 22q12.1–q13.1 by FISH. S1 nuclease mapping, primer extension, RACE, FISH Genomics High 8812417
2013 YWHAH (14-3-3η) is required for normal meiotic spindle formation in mouse oocytes; it accumulates at meiosis I and II spindles, directly interacts with α-tubulin at the metaphase II spindle (demonstrated by in situ proximity ligation assay), and morpholino-mediated knockdown of YWHAH caused deformed or absent meiotic spindles, clumped chromosomes, and failure of polar body formation in 76% of injected oocytes. Immunofluorescence, in situ proximity ligation assay, morpholino microinjection, oocyte maturation assay BMC developmental biology High 23547714
2016 Loss of Ywhah function in mice causes deafness with cochlear outer hair cell degeneration; YWHAH is highly expressed in outer and inner hair cells, spiral ganglion neurons, and retinal ganglion cells. Pathogenic variants of YWHAH reduce its capacity to bind the pro-apoptotic protein Bad, inducing mitochondrial fragmentation and increased apoptosis susceptibility, establishing that YWHAH promotes hair cell survival partly through Bad binding. Ywhah knockout mouse, auditory testing, immunohistochemistry, in vitro variant functional assays (apoptosis, mitochondrial morphology, Bad binding) Cell death discovery High 27275396
2023 YWHAH physically interacts with the transcription factor Fra-1 in gastric cancer cells, positively regulates Fra-1 mRNA and protein expression, and activates the HMGA1/PI3K/AKT/mTOR signaling pathway through Fra-1 to promote gastric cancer cell proliferation, as confirmed by co-immunoprecipitation/LC-MS/MS, whole-proteome analysis, Western blotting, and flow cytometry. Co-immunoprecipitation combined with LC-MS/MS, Western blotting, flow cytometry, siRNA knockdown Oncology research Medium 37415737
2020 miR-660-5p directly targets YWHAH (validated by dual luciferase reporter assay), and the miR-660-5p/YWHAH axis activates the PI3K/AKT pathway to promote EMT and cell cycle progression in hepatocellular carcinoma; knockdown of YWHAH partially reversed the tumor-suppressive effects of miR-660-5p inhibitor. Dual luciferase reporter assay, siRNA knockdown, in vitro and in vivo functional assays Biochemical and biophysical research communications Medium 32807493
2024 METTL14-mediated m6A methylation of YWHAH transcripts in the 5' UTR leads to recognition by the m6A reader YTHDF1 and subsequent degradation of YWHAH mRNA, thereby suppressing YWHAH expression and activating the PI3K/AKT signaling pathway to promote neuroblastoma cell activity. MeRIP-seq, RNA-seq, METTL14 knockdown, YTHDF1 functional assays, in vitro and in vivo tumor models Cell death discovery Medium 38649363
2025 YWHAH negatively regulates the MAPK/ERK signaling pathway (reducing phospho-ERK1/2 and phospho-ELK-1 levels) to suppress autophagy in colorectal cancer cells; YWHAH knockdown enhanced autophagy (upregulated ATG7, LC3II/I; downregulated p62) and inhibited migration/invasion, while ERK inhibitor or autophagy inhibitor rescued these effects, placing YWHAH upstream of ERK-mediated autophagy suppression. siRNA knockdown, YWHAH overexpression, pharmacological ERK inhibitor/agonist, autophagy assays, xenograft mouse model International journal of molecular medicine Medium 41133478
2024 GREM1 (gremlin 1) binds YWHAH in dental pulp stem cells (DPSCs) with a specific binding site identified; YWHAH promotes osteo-/dentinogenic differentiation of DPSCs in vitro and in vivo, and GREM1 negatively regulates this process through its interaction with YWHAH. Co-immunoprecipitation, polypeptide microarray, siRNA knockdown, overexpression, in vitro ALP/mineralization assays, in vivo nude mouse model The Chinese journal of dental research Medium 39221981
2025 Ywhah knockdown in 3T3-L1 pre-adipocytes notably enhanced Alpl expression even without 5-aza-2'-deoxycytidine treatment, identifying Ywhah as a negative regulator of osteogenic differentiation; its promoter methylation is altered by combined 5azaC and Wnt3a co-treatment as part of an epigenetic mechanism driving osteogenic trans-differentiation. siRNA knockdown, transcriptomic and epigenomic profiling, ALP activity assay, mineralization assay Epigenomics Low 40792537
2025 Ywhah displays strong binding affinity to cytoskeletal proteins in brown adipocytes (demonstrated by affinity purification-mass spectrometry) and is identified as a key downstream effector in the ADRβ3-COX2 signaling axis regulating brown adipocyte lipid metabolism and cytoskeletal organization. Affinity purification-mass spectrometry, WGCNA, RNA-seq, machine learning feature selection International journal of molecular sciences Low 40243609

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1997 The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 1405 9428519
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
1997 Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science (New York, N.Y.) 1191 9278512
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
1999 The DNA sequence of human chromosome 22. Nature 808 10591208
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2010 The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Developmental cell 573 21145499
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2002 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. The Journal of cell biology 452 11864996
2020 SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses. Cell 449 33080218
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
2007 Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proceedings of the National Academy of Sciences of the United States of America 360 17620599
2006 Structural basis for protein-protein interactions in the 14-3-3 protein family. Proceedings of the National Academy of Sciences of the United States of America 344 17085597
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 12 37415737
2020 Significant reductions in apoptosis-related proteins (HSPA6, HSPA8, ITGB3, YWHAH, and PRDX6) are involved in immune thrombocytopenia. Journal of thrombosis and thrombolysis 12 33047245
2016 Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration. Cell death discovery 12 27275396
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
2024 Unveiling YWHAH: A potential therapeutic target for overcoming CD8+ T cell exhaustion in colorectal cancer. International immunopharmacology 10 38796965
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
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
2025 Anti-cancer effect of midazolam via downregulating YWHAH in papillary thyroid cancer cells. Discover oncology 1 39836297
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
2023 Inhibiting miR-33b-5p Enhances Chemoresistance in Lung Adenocarcinoma by Targeting YWHAH to Regulate Epithelial-mesenchymal Transition. Anticancer research 1 38030169
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