Affinage

YWHAB

14-3-3 protein beta/alpha · UniProt P31946

Length
246 aa
Mass
28.1 kDa
Annotated
2026-06-11
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YWHAB (14-3-3β) is a phosphoserine/phosphothreonine-binding scaffold protein that integrates metabolic and oncogenic signaling through phosphorylation-dependent protein complexes (PMID:33641163). In hepatocytes it forms a complex with the glucagon receptor and directly binds FOXO1 to restrain glucagon-induced gluconeogenesis, and Ywhab-deficient mice show impaired glucose homeostasis (PMID:33641163); this brake on glucose production is reinforced at the protein level by the deubiquitinase OTUB1, which binds and deubiquitinates YWHAB to stabilize it (PMID:39270917). In cancer contexts YWHAB engages multiple growth-signaling routes: it interacts with PIK3R2 to sustain PI3K/AKT activation, proliferation, and survival in colon cancer cells (PMID:37090079), and its intact dimer is required to drive Raf/MEK/ERK (MAPK) signaling, since dimer dissociation by the compound Kuwanon A collapses this pathway in hepatocellular carcinoma cells (PMID:41090717). YWHAB also participates in protein-scaffolding interactions with SND1 and is transcriptionally controlled by IRX5 (PMID:33588586, PMID:39119237), and it directly binds the PCV2 viral protein ORF5 to suppress viral replication and associated ER stress, autophagy, and apoptosis (PMID:33096469). The structural basis of its target recognition and the rules governing its context-dependent pro- versus anti-tumorigenic outputs have not been resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2012 Low

    Early work placed YWHAB in a neurodegeneration context by citing its binding to prion protein, but it left open whether genetic variation in YWHAB contributes to disease.

    Evidence Cited prior PrP binding data plus a genetic association study of YWHAB SNPs in sporadic CJD patients

    PMID:23053962

    Open questions at the time
    • PrP binding was cited, not directly demonstrated in this study
    • the CJD association was negative, leaving no functional disease link
    • no mechanism connecting YWHAB binding to PrP pathology
  2. 2020 Medium

    Whether YWHAB has a role in host antiviral defense was addressed by identifying it as a binder and inhibitor of a viral protein.

    Evidence Pulldown/Co-IP of YWHAB with PCV2 ORF5 and overexpression/knockdown viral replication assays with ER stress/autophagy/ROS/apoptosis readouts

    PMID:33096469

    Open questions at the time
    • the binding interface and phospho-dependence are undefined
    • mechanism by which YWHAB restricts replication is not resolved
    • single lab, single study
  3. 2021 High

    The physiological metabolic role of YWHAB was established by showing it forms a receptor-bound complex that suppresses hepatic glucose production.

    Evidence AP-MS identification, Co-IP validation of GCGR/FOXO1 complex, Ywhab knockout mice with pyruvate tolerance testing, and primary hepatocyte glucose production assays

    PMID:33641163

    Open questions at the time
    • the phosphorylated residues mediating complex assembly are not mapped
    • how the complex restrains FOXO1 activity mechanistically is unresolved
    • no structural model of the GCGR-YWHAB-FOXO1 assembly
  4. 2021 Medium

    An additional scaffold partnership and its tumor relevance were probed by linking YWHAB to SND1 under circ-SMARCA5 control.

    Evidence Co-IP of SND1-YWHAB plus siRNA epistasis with proliferation/invasion/apoptosis assays and an in vivo metastasis model

    PMID:33588586

    Open questions at the time
    • YWHAB role is secondary to the circ-SMARCA5 focus
    • functional consequence of the SND1 interaction is not directly characterized
    • single lab
  5. 2023 Medium

    How YWHAB drives oncogenic growth signaling was addressed by connecting it to the PI3K/AKT axis through PIK3R2.

    Evidence Co-IP of YWHAB-PIK3R2, siRNA knockdown with CCK-8/flow cytometry/TUNEL, pathway western blots, and PIK3R2 overexpression rescue in colon cancer cells

    PMID:37090079

    Open questions at the time
    • whether the interaction is phospho-dependent is unknown
    • how YWHAB controls PIK3R2 expression versus activity is unresolved
    • single lab, single study
  6. 2024 Medium

    The upstream control of YWHAB abundance was clarified at both the protein-stability and transcriptional levels.

    Evidence Co-IP and deubiquitination assays for OTUB1-YWHAB with hepatic OTUB1 manipulation in mice; dual luciferase reporter assay for IRX5 acting on the YWHAB promoter with OE/KD breast cancer phenotypes

    PMID:39119237 PMID:39270917

    Open questions at the time
    • the ubiquitin ligase opposing OTUB1 is not identified
    • the ubiquitination sites on YWHAB are unmapped
    • IRX5 regulation tested in a single cell context
  7. 2025 Medium

    The requirement of YWHAB dimerization for MAPK signaling was demonstrated pharmacologically.

    Evidence Direct Kuwanon A-YWHAB binding and dimer dissociation assays, MAPK pathway western blots, and in vitro/in vivo HCC tumor models

    PMID:41090717

    Open questions at the time
    • the specific Raf/MEK/ERK component scaffolded by the YWHAB dimer is not defined
    • structural basis of dimer disruption is not detailed
    • single lab, single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what determines whether YWHAB acts as a tumor promoter or suppressor across tissues, and the phosphopeptide-recognition rules underlying its diverse complexes are uncharacterized.
  • no unifying structural model of YWHAB phospho-target recognition
  • context-dependent oncogenic versus suppressive outputs unexplained
  • no proteome-wide map of phospho-dependent partners

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
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1430728 Metabolism 1
Partners
FOXO1GCGRIRX5OTUB1PIK3R2SND1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 YWHAB (14-3-3β) forms a phosphorylation-dependent complex with the glucagon receptor (GCGR) and directly interacts with FOXO1, inhibiting glucagon-induced hepatic gluconeogenesis; Ywhab knockout mice show impaired glucose homeostasis under pyruvate stimulation, and deletion in primary hepatocytes increases glucose production in response to glucagon. Affinity purification/mass spectrometry (initial identification), co-immunoprecipitation (complex validation), Ywhab knockout mice with pyruvate tolerance test, primary hepatocyte glucose production assay FEBS letters High 33641163
2024 The deubiquitinase OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, thereby stabilizing YWHAB protein and suppressing hepatic gluconeogenesis. Co-immunoprecipitation (OTUB1–YWHAB interaction), deubiquitination assay, hepatic OTUB1 overexpression/deletion in mice with glucose homeostasis readouts Cellular signalling Medium 39270917
2023 YWHAB interacts with PIK3R2 (confirmed by co-immunoprecipitation), and YWHAB knockdown decreases PIK3R2 expression and reduces p-PI3K and p-AKT levels, indicating YWHAB activates the PI3K/AKT signaling pathway in colon cancer cells to promote proliferation and suppress apoptosis; PIK3R2 overexpression rescues the effects of YWHAB knockdown. Co-immunoprecipitation (YWHAB–PIK3R2 interaction), siRNA knockdown with CCK-8/flow cytometry/TUNEL readouts, western blotting for PI3K/AKT pathway markers, rescue experiment with PIK3R2 overexpression Experimental and therapeutic medicine Medium 37090079
2020 YWHAB directly interacts with the PCV2 viral protein ORF5 (confirmed by protein–protein interaction assays), and YWHAB overexpression strongly inhibits PCV2 replication; YWHAB also inhibits PCV2-induced endoplasmic reticulum stress, autophagy, ROS production, and apoptosis. Protein–protein interaction assays (pulldown/Co-IP), ectopic overexpression and gene knockdown of YWHAB, viral replication assay, ER stress/autophagy/ROS/apoptosis readouts Veterinary microbiology Medium 33096469
2021 YWHAB is an interacting partner of SND1 (confirmed by co-immunoprecipitation); in the context of circ-SMARCA5 overexpression, binding of SND1 to YWHAB is inhibited, reducing cervical cancer cell proliferation and invasion while promoting apoptosis; knockdown of YWHAB reverses the pro-tumorigenic effects caused by circ-SMARCA5 siRNA. Co-immunoprecipitation (SND1–YWHAB interaction), siRNA knockdown with proliferation/invasion/apoptosis assays (CCK-8, Transwell, Annexin V/PI), in vivo metastasis model Cell transplantation Medium 33588586
2025 The flavonoid compound Kuwanon A (KA) directly targets YWHAB and mediates dissociation of its dimer, thereby inhibiting the Raf/MEK/ERK (MAPK) signaling pathway and causing downstream cell cycle arrest and inhibition of migration/invasion in hepatocellular carcinoma cells. Direct binding assay (KA–YWHAB target identification), dimer dissociation assay, MAPK pathway western blotting, in vitro proliferation/migration/invasion assays, in vivo tumor model Cells Medium 41090717
2024 The transcription factor IRX5 regulates YWHAB expression by acting on the promoter sequence upstream of its transcription start site (shown by dual luciferase assay); YWHAB overexpression reduces migration and invasion of MDA-MB-231 breast cancer cells and downregulates vimentin expression, suggesting suppression of mesenchymal properties. Dual luciferase reporter assay (IRX5→YWHAB promoter), overexpression and knockdown with migration/invasion assays, transcriptomics of DEGs, western blotting for vimentin Oncology letters Medium 39119237
2012 14-3-3β (YWHAB) protein interacts with the N-terminal amino acids 1–38 and central hydrophobic region (amino acids 106–126) of prion protein (PrP), as reported in earlier studies cited in this paper; however, YWHAB polymorphisms were not associated with sporadic CJD susceptibility in the Korean population tested. Review of prior binding data (cited, not directly performed in this study); genetic association study of 6 YWHAB SNPs in CJD patients vs. controls (negative result for association) Molecular biology reports Low 23053962

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Circ SMARCA5 Inhibited Tumor Metastasis by Interacting with SND1 and Downregulating the YWHAB Gene in Cervical Cancer. Cell transplantation 26 33588586
2020 MiR-129-5p sensitization of lung cancer cells to etoposide-induced apoptosis by reducing YWHAB. Journal of Cancer 25 31949489
2021 The 14-3-3 protein YWHAB inhibits glucagon-induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1. FEBS letters 14 33641163
2023 YWHAB knockdown inhibits cell proliferation whilst promoting cell cycle arrest and apoptosis in colon cancer cells through PIK3R2. Experimental and therapeutic medicine 9 37090079
2020 A novel PCV2 ORF5-interacting host factor YWHAB inhibits virus replication and alleviates PCV2-induced cellular response. Veterinary microbiology 9 33096469
2024 YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells. Oncology letters 6 39119237
2012 Lack of association between 14-3-3 beta gene (YWHAB) polymorphisms and sporadic Creutzfeldt-Jakob disease (CJD). Molecular biology reports 5 23053962
2024 miR-375-3p targets YWHAB to attenuate intestine injury in neonatal necrotizing enterocolitis. Pediatric surgery international 3 38431920
2024 The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB. Cellular signalling 1 39270917
2025 Kuwanon A Targeted YWHAB in Hepatocellular Carcinoma Cells to Inhibit the Raf/MEK/ERK Signaling Pathway. Cells 0 41090717
2023 Expression of the NUP153 and YWHAB genes from their canonical promoters and alternative promoters of the LINE-1 retrotransposon in the placenta of the first trimester of pregnancy. Vavilovskii zhurnal genetiki i selektsii 0 36923475

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