Affinage

CTNNAL1

Alpha-catulin · UniProt Q9UBT7

Length
734 aa
Mass
81.9 kDa
Annotated
2026-06-09
14 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CTNNAL1 (alpha-catulin) is an alpha-catenin-related scaffold protein that couples Rho GTPase signaling to the maintenance of airway epithelial integrity and the suppression of epithelial-mesenchymal transition (PMID:12270917, PMID:38602002). It acts mechanistically as a scaffold for the Rho-specific guanine nucleotide exchange factor Lbc, binding its C-terminal region to enhance GTP-Rho loading and downstream SRF activation (PMID:12270917). In bronchial epithelium CTNNAL1 sustains a RhoA/ROCK1-dependent program that maintains expression of E-cadherin and integrins and thereby preserves intercellular and matrix adhesion, with its knockout producing denuded epithelium and structural airway damage (PMID:38602002); consistent with this adhesive/repair role, it is required for fibronectin-promoted wound repair and FAK phosphorylation (PMID:17647259) and represses ozone-induced EMT by lowering Twist1 and TGF-β1 (PMID:29791759). Loss of CTNNAL1 diverts signaling toward pathological outputs: a YAP–ROCK2 axis driving MUC5AC mucus hypersecretion and IL-4/IL-13 elevation (PMID:35092120), an hsp90 axis that raises NR3C1, ICAM-1, and NF-κB and reduces glucocorticoid sensitivity (PMID:36535402), and a ROCK1–CAL axis that suppresses CFTR expression (PMID:37715489). Its own transcription is driven by AP-2α and LEF-1 binding to its promoter (PMID:22359570).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Established the first molecular function of CTNNAL1: it is not merely an adhesion-related catenin homolog but a scaffold that links a Rho-GEF to active Rho/SRF signaling.

    Evidence Yeast two-hybrid, interaction-region mapping, co-fractionation/co-localization, GTP-Rho pulldown, and SRF-luciferase reporter in mammalian cells

    PMID:12270917

    Open questions at the time
    • Does not define which cell types depend on the Lbc scaffold function in vivo
    • No structural model of the CTNNAL1–Lbc complex
    • Link between this Rho-GEF scaffolding and the later RhoA/ROCK epithelial phenotypes not directly traced
  2. 2008 Medium

    Placed CTNNAL1 in epithelial repair, showing it is required for proliferation, wound closure, and fibronectin-induced FAK activation.

    Evidence Antisense knockdown with scratch-wound, proliferation assays, and p-FAK Western blot in human bronchial epithelial cells

    PMID:17647259

    Open questions at the time
    • Does not establish whether the FAK effect is direct or via Rho signaling
    • Mechanism of fibronectin–CTNNAL1 coupling unresolved
  3. 2012 High

    Defined the upstream transcriptional control of CTNNAL1, identifying AP-2α and LEF-1 as direct promoter-binding activators.

    Evidence EMSA, supershift, ChIP, promoter mutagenesis, and luciferase reporter in bronchial epithelial cells

    PMID:22359570

    Open questions at the time
    • Does not connect transcriptional regulation to a physiological stimulus
    • No signaling input shown to control AP-2α/LEF-1 occupancy of the CTNNAL1 promoter
  4. 2018 Medium

    Showed CTNNAL1 is a suppressor of EMT, repressing Twist1 and TGF-β1 to protect airway epithelium from ozone-induced mesenchymal transition.

    Evidence Overexpression and siRNA in airway epithelial cells under ozone exposure, EMT marker qRT-PCR, fibroblast co-culture, TGF-β1 ELISA

    PMID:29791759

    Open questions at the time
    • Pathway linking CTNNAL1 to Twist1/TGF-β1 repression not defined
    • Single-lab cellular model
  5. 2022 Medium

    Identified a YAP–ROCK2 axis downstream of CTNNAL1 loss, explaining how its deficiency drives mucus hypersecretion and type-2 cytokine elevation.

    Evidence AAV-siRNA mouse model, CTNNAL1–YAP co-IP, gain/loss in 16HBE14o- cells, pharmacological YAP/ROCK2 inhibition, MUC5AC and cytokine readouts

    PMID:35092120

    Open questions at the time
    • Direct vs indirect nature of CTNNAL1–YAP binding not structurally resolved
    • How CTNNAL1 loss shifts ROCK1→ROCK2 balance unexplained
  6. 2022 Medium

    Connected CTNNAL1 to glucocorticoid responsiveness through an hsp90 axis controlling NR3C1, ICAM-1, and NF-κB.

    Evidence CTNNAL1-siRNA mouse model, CTNNAL1–hsp90 immunoprecipitation, geldanamycin rescue, Western blots, dexamethasone comparison

    PMID:36535402

    Open questions at the time
    • Whether CTNNAL1 binding regulates hsp90 chaperone activity directly is untested
    • Reciprocal interaction validation not shown
  7. 2023 Medium

    Dissected a ROCK1–CAL axis whereby CTNNAL1 deficiency suppresses CFTR, linking the protein to ion-channel regulation in airway disease.

    Evidence CTNNAL1-siRNA mouse model, ROCK1 inhibition and RhoA activation in HBE cells, ROCK1–CAL immunoprecipitation, CFTR/ROCK Western blots

    PMID:37715489

    Open questions at the time
    • Mechanism by which CTNNAL1 sustains ROCK1 over ROCK2 not defined
    • Single-lab finding
  8. 2023 Low

    Extended CTNNAL1 function to cancer, implicating it in stem-cell properties, radioresistance, invasion, and CCL2 secretion in lung cancer and glioblastoma.

    Evidence Overexpression/knockdown in lung cancer and glioblastoma cell lines with sphere-formation, irradiation, migration/invasion assays, CCL2 ELISA

    PMID:37239133

    Open questions at the time
    • No pathway placement or upstream/downstream mechanism identified
    • Single lab, single study
    • Relationship to the airway Rho/ROCK functions untested
  9. 2024 Medium

    Consolidated the structural role of CTNNAL1, showing it maintains epithelial adhesion molecule expression and integrity via RhoA/ROCK1 in vivo.

    Evidence AAV-RNAi knockout mice, stable siRNA HBEC line, HE staining, adhesion assays, ROCK inhibitor Y27632 rescue, Western blots for E-cadherin/integrins/RhoA/ROCK1

    PMID:38602002

    Open questions at the time
    • Does not resolve how the Lbc-scaffolding activity feeds into RhoA/ROCK1 in epithelium
    • Direct CTNNAL1 binding partners in the adhesion complex not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the single biochemical activity of CTNNAL1 (Lbc/Rho-GEF scaffolding) mechanistically determines the divergent ROCK1 vs ROCK2 outputs and its multiple binding partners (YAP, hsp90, ROCK1–CAL) remains unresolved.
  • No structural model linking scaffold function to downstream effector selection
  • Whether YAP, hsp90, and CAL bind CTNNAL1 directly or via Rho-pathway intermediates is unclear
  • No reconstitution of CTNNAL1's role in ROCK1/ROCK2 balance

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
GOPCHSP90LBC/AKAP13ROCK1YAP1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Alpha-catulin (CTNNAL1) directly interacts with the C-terminal region of Lbc, a Rho-specific guanine nucleotide exchange factor; the required interaction regions were mapped, complex formation was detected in mammalian cells by co-fractionation and co-localization, and alpha-catulin co-expression enhances Lbc-induced GTP-Rho formation and serum response factor (SRF) activation, functioning as a scaffold for Lbc. Yeast two-hybrid screen, subcellular co-fractionation, intracellular co-localization, co-immunoprecipitation in mammalian cells, transcriptional reporter assay (SRF-luciferase), in vivo GTP-Rho pulldown assay The Journal of biological chemistry High 12270917
2008 CTNNAL1 is required for wound repair and proliferation of human bronchial epithelial cells (HBECs); antisense oligonucleotide (ASO) knockdown of CTNNAL1 decelerates repair velocity and proliferation, blocks fibronectin-promoted wound repair, and inhibits fibronectin-induced FAK phosphorylation, placing CTNNAL1 in the fibronectin–FAK signaling axis. Antisense oligonucleotide knockdown, scratch-wound assay, cell proliferation assay, Western blot for FAK phosphorylation Journal of cellular biochemistry Medium 17647259
2012 Transcription factors AP-2α and LEF-1 bind to the CTNNAL1 promoter and drive its transcription in human bronchial epithelial cells; binding was confirmed by EMSA, antibody supershift, and ChIP, and site-directed mutagenesis of the AP-2α and LEF-1 sites in the CTNNAL1 promoter reduced promoter activity. EMSA, antibody supershift assay, chromatin immunoprecipitation (ChIP), site-directed mutagenesis of promoter binding sites, luciferase reporter assay, antisense oligonucleotide knockdown of AP-2α and LEF-1 PloS one High 22359570
2018 CTNNAL1 inhibits ozone-induced epithelial-mesenchymal transition (EMT) in airway epithelial cells; overexpression reverses EMT features, represses Twist1 mRNA expression, and reduces TGF-β1 secretion, while silencing of CTNNAL1 exacerbates ozone-induced EMT and enhances functional changes in co-cultured lung fibroblasts. Stable transfection (overexpression and siRNA silencing), ozone exposure model, EMT marker analysis, co-culture assay with lung fibroblasts, qRT-PCR for Twist1/Twist2/Snail/Slug, ELISA for TGF-β1 Experimental physiology Medium 29791759
2022 CTNNAL1 interacts with YAP (Yes-associated protein) as confirmed by co-immunoprecipitation; CTNNAL1 silencing downregulates YAP expression and increases ROCK2, leading to mucus hypersecretion (MUC5AC) and IL-4/IL-13 elevation; YAP inhibition reduces MUC5AC, IL-4, and IL-13 and decreases ROCK2, placing CTNNAL1 upstream of a YAP–ROCK2 pathway controlling mucus secretion. AAV-delivered siRNA mouse model, co-immunoprecipitation (CTNNAL1–YAP interaction), CTNNAL1 overexpression/silencing in 16HBE14o- cells, pharmacological YAP and ROCK2 inhibition, ELISA for cytokines, PAS staining for goblet cells, MUC5AC measurement Journal of cellular and molecular medicine Medium 35092120
2022 CTNNAL1 physically interacts with hsp90 (confirmed by immunoprecipitation); CTNNAL1 silencing upregulates hsp90 expression and increases NR3C1, ICAM-1, and NF-κB (p-p65) levels, reducing glucocorticoid sensitivity; hsp90 inhibitor geldanamycin rescues these effects, placing hsp90 downstream of CTNNAL1 in regulating airway inflammation and steroid responsiveness. CTNNAL1-siRNA mouse model, immunoprecipitation (CTNNAL1–hsp90), pharmacological hsp90 inhibition with geldanamycin, Western blot for NR3C1/ICAM-1/p-p65, dexamethasone treatment comparison Life sciences Medium 36535402
2023 CTNNAL1 deficiency decreases CFTR expression through a ROCK1–CAL signaling axis: CTNNAL1 silencing reduces ROCK1 activity (while increasing ROCK2), ROCK1 inhibition reduces CFTR expression, RhoA activation increases CFTR, CAL (CFTR-associated ligand) expression increases upon CTNNAL1 silencing, and immunoprecipitation confirms ROCK1–CAL interaction; CAL inhibition restores CFTR expression without affecting ROCK1. CTNNAL1-siRNA mouse model, ROCK1 pharmacological inhibition and RhoA activation in HBE cells, immunoprecipitation (ROCK1–CAL interaction), Western blot for CFTR/ROCK1/ROCK2/CAL, in vitro and in vivo experiments Acta biochimica et biophysica Sinica Medium 37715489
2024 CTNNAL1 maintains structural integrity of bronchial epithelial cells via the RhoA/ROCK1 pathway; CTNNAL1 knockout mice show denuded epithelial cells and airway structural damage; CTNNAL1 silencing reduces E-cadherin, integrin β1, and integrin β4 expression, weakens extracellular matrix and intercellular adhesion, and decreases RhoA/ROCK1 levels; ROCK inhibitor Y27632 abolishes ozone-induced adhesion molecule upregulation in CTNNAL1-overexpressing cells, confirming ROCK1 as the downstream effector. AAV-RNAi mouse knockout, stable siRNA-transfected HBEC cell line, HE staining, cell proliferation and adhesion assays, Western blot for E-cadherin/integrins/RhoA/ROCK1, pharmacological ROCK inhibition with Y27632, ozone stress model Acta biochimica et biophysica Sinica Medium 38602002
2023 CTNNAL1 regulates cancer stem cell properties, radiation resistance, migration, invasion, and CCL2 chemokine secretion in lung cancer and glioblastoma cells; loss or gain of CTNNAL1 modulates EMT markers and stem cell characteristics. CTNNAL1 overexpression and knockdown in lung cancer and glioblastoma cell lines, sphere-formation assay, irradiation resistance assay, migration/invasion assay, CCL2 ELISA Biomedicines Low 37239133

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Association of Lbc Rho guanine nucleotide exchange factor with alpha-catenin-related protein, alpha-catulin/CTNNAL1, supports serum response factor activation. The Journal of biological chemistry 53 12270917
1998 Identification and chromosomal localization of CTNNAL1, a novel protein homologous to alpha-catenin. Genomics 33 9806841
2008 Wound repair and proliferation of bronchial epithelial cells regulated by CTNNAL1. Journal of cellular biochemistry 22 17647259
2013 Associations of TCF12, CTNNAL1 and WNT10B gene polymorphisms with litter size in pigs. Animal reproduction science 17 23820070
2022 CTNNAL1 participates in the regulation of mucus overproduction in HDM-induced asthma mouse model through the YAP-ROCK2 pathway. Journal of cellular and molecular medicine 14 35092120
2018 CTNNAL1 inhibits ozone-induced epithelial-mesenchymal transition in human bronchial epithelial cells. Experimental physiology 13 29791759
2012 Identification of transcription factors regulating CTNNAL1 expression in human bronchial epithelial cells. PloS one 13 22359570
2018 Genetic effect and combined genotype effect of ESR, FSHβ, CTNNAL1 and miR-27a loci on litter size in a Large White population. Animal biotechnology 11 30178695
2020 Genetic variants in RET, ARHGEF3 and CTNNAL1, and relevant interaction networks, contribute to the risk of Hirschsprung disease. Aging 9 32139661
2023 Regulation of Cancer Stem Cells and Epithelial-Mesenchymal Transition by CTNNAL1 in Lung Cancer and Glioblastoma. Biomedicines 7 37239133
2022 CTNNAL1 enhances glucocorticoid sensitivity in HDM-induced asthma mouse model through deactivating hsp90 signaling pathway. Life sciences 4 36535402
2024 CTNNAL1 promotes the structural integrity of bronchial epithelial cells through the RhoA/ROCK1 pathway. Acta biochimica et biophysica Sinica 2 38602002
2012 [Relevance of the expression of CTNNAL1 and the resistance of respiratory tract in rat with airway hyperresponsiveness]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 2 23000764
2023 CTNNAL1 deficiency suppresses CFTR expression in HDM-induced asthma mouse model through ROCK1-CAL signaling pathway. Acta biochimica et biophysica Sinica 1 37715489

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