Affinage

CGN

Cingulin · UniProt Q9P2M7

Length
1203 aa
Mass
137.1 kDa
Annotated
2026-06-09
14 papers in source corpus 3 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cingulin (CGN) is a cytoplasmic tight junction scaffold that links the junctional adaptor ZO-1 to the actomyosin and microtubule cytoskeletons in epithelial cells (PMID:37566083). It controls the junctional accumulation and protein abundance of claudin-2, and this regulation is independent of ZO-1, as CGN or its relative CGNL1 — but not ZO-1 — rescue the loss-of-CGN phenotype (PMID:37566083). CGN is dispensable for overall epithelial paracellular barrier function, with its loss producing only a modest increase in transepithelial resistance (PMID:37566083). Beyond its junctional role, CGN restrains the RhoA/ROCK signaling pathway: loss of CGN activates RhoA/ROCK to promote cell migration and invasion, and restoring CGN suppresses these behaviors in cancer cells (PMID:34830864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2021 Medium

    Established that CGN is a post-transcriptionally regulated suppressor of cell motility, defining its link to RhoA/ROCK signaling in cancer.

    Evidence dual-luciferase 3'UTR reporter, miR-125b/CGN overexpression and knockdown, migration/invasion assays and xenografts in colorectal cancer cells

    PMID:34830864

    Open questions at the time
    • the molecular step by which CGN restrains RhoA is not defined (no GEF/GAP or direct binding partner identified)
    • link is correlative for the signaling axis rather than reconstituted
    • generality beyond colorectal cancer untested at this point
  2. 2023 Medium

    Defined CGN's core junctional mechanism by separating its cytoskeletal-tethering and claudin-2-regulatory functions from barrier maintenance and from ZO-1.

    Evidence CRISPR knockout of CGN/CGNL1 in MDCK cells with calcium switch, transepithelial resistance, dextran permeability, and overexpression rescue

    PMID:37566083

    Open questions at the time
    • mechanism by which CGN controls claudin-2 protein levels (transcriptional vs stability) unresolved
    • single cell line (MDCK) and single lab
    • direct binding interfaces to ZO-1, actomyosin, and microtubules not mapped here
  3. 2025 Low

    Extended the CGN–RhoA/ROCK suppressor axis to ovarian cancer and nominated CGN as a druggable target of a natural compound.

    Evidence polyphyllin H treatment with proteomics/protein sequencing, proliferation/invasion/migration assays, CDX and PDX models

    PMID:40773225

    Open questions at the time
    • CGN-RhoA/Rock2 link inferred from protein sequencing, not validated by mutagenesis or reconstitution
    • whether polyphyllin H acts directly or indirectly on CGN is unknown
    • not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CGN mechanistically couples to RhoA/ROCK signaling and how its junctional scaffolding role connects to its motility-suppressing role remain unresolved.
  • no direct effector linking CGN to RhoA regulation identified
  • structural basis of cytoskeletal and ZO-1 tethering not characterized in the corpus
  • mechanism controlling claudin-2 abundance unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 1
Partners
CGNL1ZO-1
Complex memberships
tight junction

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Knockout of CGN (cingulin) and/or CGNL1 (paracingulin) in MDCK kidney epithelial cells causes a modest but significant increase in transepithelial resistance and decreased junctional accumulation of claudin-2, with reduced claudin-2 protein levels; this phenotype was rescued by CGN or CGNL1 overexpression but not by ZO-1 overexpression, establishing that CGN regulates claudin-2 junctional localization and expression independently of ZO-1. CRISPR knockout in MDCK cells, calcium switch assay, transepithelial resistance measurement, dextran permeability assay, rescue by overexpression Cells Medium 37566083
2023 CGN (cingulin) plays a role in tethering ZO-1 to the actomyosin and microtubule cytoskeletons at tight junctions, and is dispensable for overall epithelial barrier function in MDCK cells. Knockout in MDCK cells, transepithelial resistance measurement, permeability assays Cells Medium 37566083
2021 CGN (cingulin) is a direct target of miR-125b in colorectal cancer cells; miR-125b suppresses CGN expression via its 3'UTR (validated by dual-luciferase reporter assay), and CGN loss activates the RhoA/ROCK pathway to promote cell migration and invasion. Dual-luciferase reporter assay, RNA-seq, overexpression/knockdown of miR-125b and CGN in CRC cells, in vitro migration/invasion assays, in vivo xenograft Cancers Medium 34830864
2025 CGN (cingulin) upregulation by polyphyllin H blocks the RhoA/Rock2 signaling pathway in ovarian cancer cells, inhibiting proliferation, invasion, and migration; protein sequencing identified CGN as the mechanistic target mediating polyphyllin H's anti-tumor effects. CCK-8 proliferation assay, in vitro invasion/migration assays, CDX and PDX mouse models, protein sequencing/proteomics, in vivo tumor growth measurement International journal of surgery (London, England) Low 40773225

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN. Cancers 30 34830864
2013 Life without tRNAArg-adenosine deaminase TadA: evolutionary consequences of decoding the four CGN codons as arginine in Mycoplasmas and other Mollicutes. Nucleic acids research 28 23658230
2022 Single-cell RNA Sequencing Identified Novel Nr4a1+ Ear2+ Anti-Inflammatory Macrophage Phenotype under Myeloid-TLR4 Dependent Regulation in Anti-Glomerular Basement Membrane (GBM) Crescentic Glomerulonephritis (cGN). Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 35484716
2015 Transformation pathways in high-pressure solid nitrogen: from molecular N2 to polymeric cg-N. The Journal of chemical physics 15 25747092
2022 Biophysical interaction between lanthanum chloride and (CG)n or (GC)n repeats: A reversible B-to-Z DNA transition. International journal of biological macromolecules 11 35809677
2006 Isolation, mapping and identification of SNPs for four genes (ACP6, CGN, ANXA9, SLC27A3) from a bovine QTL region on BTA3. Cytogenetic and genome research 7 16717448
2023 Knock Out of CGN and CGNL1 in MDCK Cells Affects Claudin-2 but Has a Minor Impact on Tight Junction Barrier Function. Cells 6 37566083
2016 Where have all the inosines gone? Conflicting evidence for A-to-I editing of the anticodon of higher eukaryotic tRNAACGArg questions the dogma of a universal wobble-mediated decoding of CGN codons. IUBMB life 5 27029281
2021 Hepatic antioxidant activity, immunomodulation, and pro-anti-inflammatory cytokines manipulation of κ-carrageenan (κ-CGN) in cobia, Rachycentron canadum against Lactococcus garvieae. Fish & shellfish immunology 3 34562582
2024 TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism. iScience 2 39628587
1996 [Evaluation of factors influencing platelet aggregation in patients with chronic glomerulonephritis (CGN)]. Przeglad lekarski 2 8754409
2024 Arginines of the CGN codon family are Achilles' heels of cancer genes. Scientific reports 1 38778164
1996 [Evaluation of platelet membrane structure in patients with chronic glomerulonephritis (CGN)]. Przeglad lekarski 1 8754408
2025 Polyphyllin H inhibits malignant progression of ovarian cancer in patient-derived xenograft mouse models by regulating CGN/RhoA/Rock2 axis: an experimental research. International journal of surgery (London, England) 0 40773225

Missed literature

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