Affinage

CTNNA3

Catenin alpha-3 · UniProt Q9UI47

Length
895 aa
Mass
99.8 kDa
Annotated
2026-06-09
32 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CTNNA3 (αT-catenin) is an adherens-junction catenin that links cadherin-based adhesion complexes to the actin cytoskeleton and constrains growth-promoting signaling across cardiac, epithelial, and tumor contexts (PMID:35536443, PMID:37126683). Its expression is established transcriptionally by GATA-4 and MEF2C acting at the CTNNA3 promoter, with one GATA box absolutely required for high promoter activity in cardiac cells; the isolated promoter recapitulates tissue-specific αT-catenin expression in vivo (PMID:15302915). MEF2C-driven CTNNA3 transcription is potentiated by fortilin, which binds the N-terminal region of MEF2C, protects it from ubiquitin-proteasome degradation, promotes its activating Ser59 phosphorylation, and thereby increases MEF2C occupancy and RNA Pol II loading at the CTNNA3 locus (PMID:41933733). At the protein level, fortilin additionally binds CTNNA3 directly and shields it from phosphorylation-triggered ubiquitination and proteasomal turnover, defining CTNNA3 as a pro-survival molecule whose loss induces apoptosis (PMID:39747445); this stabilizing influence is opposed by UBD, which drives CTNNA3 ubiquitination and degradation in hepatocellular carcinoma (PMID:41076572). In the cardiomyocyte intercalated disc, site-specific phosphorylation of CTNNA3 governs its localization and its regulation of cell-cell conductance and adhesion, with hyperphosphorylation observed in dilated cardiomyopathy (PMID:37126683). Functionally, CTNNA3 is a negative regulator of YAP/TAZ signaling and cardiomyocyte proliferation—its deficiency upregulates YAP and enhances neonatal heart regeneration (PMID:34036899, PMID:40765350)—and it acts as a tumor suppressor that restrains cell migration and invasion, in part through inhibition of Akt signaling, with its assembly into the CDH1-CTNNB1-CTNNA3 adhesion complex antagonized by SPATA33 (PMID:24100690, PMID:26882563, PMID:35536443). CTNNA3 is also subject to placental genomic imprinting with preferential maternal-allele expression in villous cytotrophoblast (PMID:15533819).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Established how CTNNA3 transcription is controlled and restricted to specific tissues, identifying GATA-4 and MEF2C as direct activators of its promoter.

    Evidence Promoter mutagenesis in P19/HL-1 cells, in vivo GATA-4 binding, and transgenic LacZ reporter mice

    PMID:15302915

    Open questions at the time
    • Did not address cofactors required for MEF2C activity at the locus
    • No post-transcriptional or protein-level regulation defined
  2. 2004 Medium

    Showed CTNNA3 is epigenetically regulated, revealing tissue- and cell-type-specific genomic imprinting in placenta.

    Evidence Allele-specific RT-PCR on informative heterozygous samples with immunostaining of trophoblast subtypes

    PMID:15533819

    Open questions at the time
    • Imprinting control region/mechanism not mapped
    • Functional consequence of monoallelic expression unknown
  3. 2013 Medium

    Provided the first direct functional evidence that CTNNA3 suppresses tumor cell behavior, framing it as a tumor suppressor.

    Evidence Mutant CTNNA3 expression and siRNA silencing with migration/invasion assays in head and neck squamous carcinoma cells

    PMID:24100690

    Open questions at the time
    • Downstream effector pathway not defined
    • No in vivo validation in this study
  4. 2015 Low

    Implicated CTNNA3 in immune/allergen sensitization signaling beyond its adhesion role.

    Evidence siRNA knockdown in mononuclear cells with flow cytometry for CD63/CD203c after PMA stimulation

    PMID:26188062

    Open questions at the time
    • Single knockdown experiment without pathway characterization
    • Mechanism linking CTNNA3 to basophil activation markers unknown
  5. 2016 Medium

    Connected CTNNA3 tumor suppression to a defined signaling axis (Akt) and to upstream microRNA control.

    Evidence Overexpression/knockdown in HCC lines, miR-425 3′UTR luciferase reporter, Western blots, and xenografts

    PMID:26882563

    Open questions at the time
    • Direct biochemical link between CTNNA3 and Akt not resolved
    • Whether adhesion-complex assembly mediates the effect not tested
  6. 2016 Low

    Tested whether CTNNA3 maintains cytoskeletal integrity and adhesion in a non-canonical (Schwann cell) context.

    Evidence Transient siRNA knockdown in cultured Schwann cells with cytoskeletal and E-cadherin staining

    PMID:27765635

    Open questions at the time
    • Single knockdown without rescue or pathway placement
    • Phenotype not validated in vivo
  7. 2021 Medium

    Positioned CTNNA3 as a negative regulator of YAP/TAZ and as an autophagy substrate, integrating its level into cell-type-specific transcriptional responses.

    Evidence Autophagy modulation in cells with varying CTNNA3, YAP/TAZ activity readouts, and a mathematical model validated experimentally

    PMID:34036899

    Open questions at the time
    • Mechanism by which CTNNA3 sequesters/regulates YAP/TAZ not detailed
    • Autophagy receptor mediating CTNNA3 degradation not identified
  8. 2022 Medium

    Identified a direct binding partner (SPATA33) that controls CTNNA3 incorporation into the cadherin adhesion complex.

    Evidence Co-IP, CRISPR Spata33 knockout in TM4 Sertoli cells, scratch/migration assays, flow cytometry, and phalloidin F-actin staining

    PMID:35536443

    Open questions at the time
    • Binding interface on CTNNA3 not mapped
    • Whether SPATA33 regulation operates in other tissues unknown
  9. 2023 High

    Defined how CTNNA3 phosphorylation governs its localization and function at the cardiomyocyte intercalated disc, linking it to dilated cardiomyopathy.

    Evidence Phosphoproteomics of human LV tissue plus ex vivo cardiomyocytes and in vivo AAV9 overexpression of phospho-variants in mice

    PMID:37126683

    Open questions at the time
    • Kinase(s) responsible for ICD-specific phosphorylation not identified
    • Causal role of hyperphosphorylation in human DCM not established
  10. 2025 High

    Established CTNNA3 as a pro-survival protein and identified fortilin as a direct stabilizer protecting it from phosphorylation-dependent degradation.

    Evidence Co-IP, PLA, MST, BLI, fortilin/CTNNA3 silencing, phospho-null (5A)/mimetic (5D) mutants, proteasome inhibition, and apoptosis assays

    PMID:39747445

    Open questions at the time
    • E3 ligase driving CTNNA3 ubiquitination not identified in this study
    • Kinase linking phosphorylation to degradation not defined
  11. 2025 Medium

    Demonstrated that CTNNA3 restrains cardiomyocyte proliferation in vivo and that its loss enhances neonatal heart regeneration via YAP.

    Evidence Ctnna3 knockout neonatal mouse apex-resection model with proliferation assays and YAP expression analysis

    PMID:40765350

    Open questions at the time
    • Molecular link between CTNNA3 and YAP regulation not resolved
    • Whether effect persists into adult regeneration unknown
  12. 2025 Medium

    Identified UBD as a negative regulator that degrades CTNNA3, placing CTNNA3 downstream in a UBD/CTNNA3 axis controlling HCC malignancy.

    Evidence In vitro ubiquitination assay, UBD/CTNNA3 knockdown epistasis, proliferation/migration/invasion assays, and EMT marker Western blots

    PMID:41076572

    Open questions at the time
    • Whether UBD acts directly as the degradation signal or recruits an E3 not defined
    • Relationship to fortilin-mediated stabilization not tested
  13. 2026 High

    Resolved the transcriptional arm of CTNNA3 regulation, showing fortilin acts as a MEF2C cofactor that stabilizes and activates MEF2C to drive CTNNA3 expression.

    Evidence MST, PLA, in vitro/in vivo Co-IP, docking, D25A mutagenesis, ubiquitination assays, CTNNA3 promoter luciferase, and RNA Pol II ChIP

    PMID:41933733

    Open questions at the time
    • How fortilin partitions between MEF2C (nuclear) and CTNNA3 (junctional) regulation not addressed
    • Physiological contexts where this axis dominates not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The kinase and E3 ligase machinery that couples CTNNA3 phosphorylation to its ubiquitination and turnover remain unidentified, and the molecular basis of its YAP/TAZ regulation is undefined.
  • No CTNNA3-directed kinase identified
  • Direct E3 ligase versus UBD adaptor role unresolved
  • Structural/biochemical mechanism of YAP/TAZ suppression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CDH1CTNNB1MEF2CSPATA33TPT1UBD
Complex memberships
CDH1-CTNNB1-CTNNA3 adhesion complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 GATA-4 and MEF2C transcription factors directly activate the CTNNA3 (alphaT-catenin) promoter; one GATA box is absolutely required for high promoter activity in cardiac HL-1 cells, and GATA-4 specifically binds and activates the CTNNA3 promoter in vivo. The isolated promoter region directs tissue-specific expression in transgenic mice concordant with endogenous alphaT-catenin expression. Co-transfection studies with wild-type and mutant promoter constructs in P19 and HL-1 cells; in vivo promoter analysis in transgenic mice with LacZ reporter; GATA-4 in vivo binding assay Nucleic acids research High 15302915
2004 CTNNA3 is subject to genomic imprinting in placenta with preferential expression of the maternal allele in villus cytotrophoblast; expression in extravillous trophoblast is biallelic; expression is lost in villus syncytiotrophoblast and in extravillous trophoblast following epithelial-mesenchymal transition. This imprinting pattern mirrors that of p57KIP2, suggesting a shared conserved regulatory mechanism. Allele-specific RT-PCR using informative heterozygous samples; immunostaining for alphaT-catenin, p57KIP2, and low-molecular-weight cytokeratin Gene expression patterns : GEP Medium 15533819
2013 CTNNA3 acts as a tumour suppressor in laryngeal carcinoma; cells producing mutated forms of CTNNA3 or cells where CTNNA3 is silenced show increased migration and invasive ability, establishing a direct role for CTNNA3 in suppressing cell migration and invasion. Functional studies with mutant CTNNA3 expression and siRNA-mediated silencing in head and neck squamous cell carcinoma cells; migration and invasion assays Nature communications Medium 24100690
2016 CTNNA3 inhibits proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cell lines by suppressing Akt signaling, decreasing PCNA and MMP-9, and increasing p21Cip1/Waf1. CTNNA3 is directly targeted and repressed by miR-425 binding to the 3′UTR of CTNNA3 mRNA. Both the tumour-suppressor function of CTNNA3 and the oncogenic function of miR-425 were confirmed in HCC xenografts in nude mice. CTNNA3 overexpression/knockdown in HCC cell lines; luciferase 3′UTR reporter assay for miR-425; Western blot for Akt, PCNA, MMP-9, p21; xenograft mouse model Oncotarget Medium 26882563
2016 Knockdown of CTNNA3 (alphaT-catenin) in Schwann cells causes cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like changes, consistent with a role for CTNNA3 in maintaining cytoskeletal integrity and cell-cell adhesion in peripheral nerve sheath cells. Transient siRNA knockdown of CTNNA3 in cultured Schwann cells; cytoskeletal staining; E-cadherin immunostaining The American journal of pathology Low 27765635
2015 Knockdown of CTNNA3 in mononuclear cells results in upregulation of CD63 and CD203c upon PMA stimulation, suggesting CTNNA3 plays a role in regulating allergen sensitization signaling. siRNA knockdown of CTNNA3 in mononuclear cells; flow cytometry for CD63 and CD203c after PMA stimulation Journal of immunology Low 26188062
2021 CTNNA3 levels determine cell-type-specific YAP1-WWTR1/TAZ transcriptional responses to autophagy perturbations. CTNNA3 (like CTNNA1) acts as a negative regulator of YAP1-WWTR1/TAZ and is itself an autophagy substrate; this relationship was integrated into a mathematical model validated by experimental data. Experimental autophagy modulation in cells with varying CTNNA3 levels; YAP1/TAZ activity measurements; mathematical modeling validated against experimental observations Autophagy Medium 34036899
2022 SPATA33 physically interacts with CTNNA3 in TM4 Sertoli cells. This interaction inhibits the formation of the CDH1-CTNNB1-CTNNA3 adhesion complex, thereby weakening cell-cell adhesion and promoting cell migration. SPATA33 knockout disrupts F-actin formation, decreases G1-phase cells, and impairs cell migration. Co-immunoprecipitation (protein IP); CRISPR-Cas9 Spata33 knockout in TM4 cells; cell wound scratch assay; flow cytometry; phalloidin staining for F-actin Cell and tissue research Medium 35536443
2023 CTNNA3 is hyperphosphorylated at specific residues in the intercalated disc (ICD) of cardiomyocytes in dilated cardiomyopathy (DCM). Phosphorylation at these residues is required for maintaining CTNNA3 protein localization at the cardiomyocyte ICD to regulate cell-cell conductance and adhesion, as demonstrated by ex vivo cardiomyocytes and in vivo AAV9-mediated overexpression of wild-type vs. phosphomutant CTNNA3 in mice. Mass spectrometry phosphoproteomics of human LV tissue; ex vivo cardiomyocyte experiments; in vivo AAV9-mediated overexpression of CTNNA3 phospho-variants in mouse heart; localization imaging and conductance/adhesion assays Proceedings of the National Academy of Sciences of the United States of America High 37126683
2025 Fortilin specifically binds CTNNA3 (but not CTNNA1, CTNNA2, or CTNNB1) via direct protein-protein interaction. Fortilin protects CTNNA3 against phosphorylation, subsequent ubiquitination, and proteasome-mediated degradation. Silencing of CTNNA3 causes apoptosis in 293T cells, identifying CTNNA3 as a pro-survival molecule. Absence of fortilin accelerates CTNNA3 phosphorylation and degradation. Co-immunoprecipitation western blot; proximity ligation assay; microscale thermophoresis; biolayer interferometry; siRNA silencing of fortilin and CTNNA3; phospho-null (5A) and phospho-mimetic (5D) CTNNA3 mutants; proteasome inhibitor experiments; apoptosis assays in 293T cells and fortilin-deficient THP1 cells Communications biology High 39747445
2025 Ctnna3 deficiency in neonatal mice promotes cardiomyocyte proliferation and enhances heart regeneration after apex resection. The mechanism involves upregulation of YAP (Yes-associated protein) expression in Ctnna3-deficient P7 hearts. Ctnna3 knockout neonatal mouse model; heart apex resection; cardiomyocyte proliferation assays; YAP expression analysis Frontiers in bioscience (Landmark edition) Medium 40765350
2025 UBD (ubiquitin D) promotes ubiquitination and proteasomal degradation of CTNNA3 in HCC cells, thereby reducing CTNNA3 protein levels. UBD knockdown restores CTNNA3 expression and suppresses HCC proliferation, migration, invasion, and EMT; CTNNA3 knockdown counteracts these inhibitory effects, placing CTNNA3 downstream of UBD in a UBD/CTNNA3 regulatory axis. In vitro ubiquitination assay; siRNA knockdown of UBD and CTNNA3 in HCC cells; CCK-8, colony formation, EdU, and transwell assays; Western blot for EMT markers Cell journal Medium 41076572
2026 Fortilin specifically binds the N-terminal region (amino acids 1–85) of MEF2C (but not MEF2A, MEF2B, or MEF2D) via a binding interface involving aspartic acid 25 of fortilin (D25A mutation weakens binding). Fortilin protects MEF2C from ubiquitination and proteasomal degradation and promotes MEF2C serine 59 phosphorylation (required for transcriptional activity) in a binding-dependent manner. Loss of fortilin reduces MEF2C binding to nuclear DNA, decreases CTNNA3 promoter-driven luciferase activity in an MEF2C-dependent fashion, and lowers RNA polymerase II occupancy at the CTNNA3 locus, establishing fortilin as a transcriptional cofactor of MEF2C that drives CTNNA3 transcription. Microscale thermophoresis; proximity ligation assay; in vitro and in vivo co-immunoprecipitation western blot; molecular docking; site-directed mutagenesis (D25A); ubiquitination assays; CTNNA3 promoter-driven luciferase reporter; chromatin immunoprecipitation (RNA Pol II occupancy); fortilin loss-of-function The Journal of biological chemistry High 41933733

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 75 19187332
2013 Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas. Nature communications 71 24100690
2007 Genetic association of CTNNA3 with late-onset Alzheimer's disease in females. Human molecular genetics 59 17761686
2016 CTNNA3 is a tumor suppressor in hepatocellular carcinomas and is inhibited by miR-425. Oncotarget 45 26882563
2004 GATA-4 and MEF2C transcription factors control the tissue-specific expression of the alphaT-catenin gene CTNNA3. Nucleic acids research 43 15302915
2002 Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy. Human genetics 41 12596047
2015 CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies. The Journal of allergy and clinical immunology 39 26073756
2014 A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder. Journal of neurodevelopmental disorders 39 25050139
2012 CTNNA3 (α-catenin) gene variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population. Toxicological sciences : an official journal of the Society of Toxicology 32 22977168
2005 Interaction between the alpha-T catenin gene (VR22) and APOE in Alzheimer's disease. Journal of medical genetics 31 16199552
2016 Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor. The American journal of pathology 26 27765635
2023 Proteomics and phosphoproteomics of failing human left ventricle identifies dilated cardiomyopathy-associated phosphorylation of CTNNA3. Proceedings of the National Academy of Sciences of the United States of America 25 37126683
2021 Expression of ovine CTNNA3 and CAP2 genes and their association with growth traits. Gene 24 34481004
2004 Differential downregulation of alphaT-catenin expression in placenta: trophoblast cell type-dependent imprinting of the CTNNA3 gene. Gene expression patterns : GEP 22 15533819
2015 Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy. Journal of immunology (Baltimore, Md. : 1950) 20 26188062
2014 Polymorphisms in recent GWA identified asthma genes CA10, SGK493, and CTNNA3 are associated with disease severity and treatment response in childhood asthma. Immunogenetics 20 24407380
2004 Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer's disease. Neuroscience letters 20 15039120
2025 Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis. Communications biology 19 39747445
2007 Is alpha-T catenin (VR22) an Alzheimer's disease risk gene? Journal of medical genetics 17 17209133
2011 Alpha T-catenin (CTNNA3): a gene in the hand is worth two in the nest. Cellular and molecular life sciences : CMLS 14 21598020
2007 Alpha-T-catenin (CTNNA3) displays tumour specific monoallelic expression in urothelial carcinoma of the bladder. Genes, chromosomes & cancer 13 17366617
2022 First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B. HGG advances 7 35199045
2021 Cell type-specific YAP1-WWTR1/TAZ transcriptional responses after autophagy perturbations are determined by levels of α-catenins (CTNNA1 and CTNNA3). Autophagy 7 34036899
2018 Analysis of Single Nucleotide Polymorphisms of STK32B, PPARGC1A and CTNNA3 Gene With Sporadic Parkinson's Disease Susceptibility in Chinese Han Population. Frontiers in neurology 5 29899728
2017 No rare deleterious variants from STK32B, PPARGC1A, and CTNNA3 are associated with essential tremor. Neurology. Genetics 5 30584593
2022 SPATA33 affects the formation of cell adhesion complex by interacting with CTNNA3 in TM4 cells. Cell and tissue research 2 35536443
2016 A case of polimalformed fetus with a microdeletion of CTNNA3 gene. Journal of prenatal medicine 1 28725342
2026 Paediatric patient with FLNC and CTNNA3 variants presenting with frequent premature ventricular contractions and systolic dysfunction: a case report. Cardiology in the young 0 41891175
2026 Fortilin binds and stabilizes MEF2C, activates it through phosphorylation, and drives transcription of the cell structural and survival protein CTNNA3. The Journal of biological chemistry 0 41933733
2025 Ctnna3 Deficiency Promotes Heart Regeneration by Enhancing Cardiomyocyte Proliferation in Neonatal Mice. Frontiers in bioscience (Landmark edition) 0 40765350
2025 UBD Promotes The Proliferation and Epithelial-Mesenchymal Transition of Hepatocellular Carcinomas via Regulating CTNNA3. Cell journal 0 41076572
2024 Potential role of CTNNA3 and FRMPD4 in vascular tumorous thrombosis of colon adenocarcinoma. Indian journal of pathology & microbiology 0 38727409

Missed literature

Know a paper Affinage missed for CTNNA3? Flag it for the maintainers and the community.

No submissions yet.