Affinage

CLDN2

Claudin-2 · UniProt P57739

Length
230 aa
Mass
24.5 kDa
Annotated
2026-06-09
18 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLDN2 encodes a pore-forming tight junction protein whose abundance is tightly controlled at transcriptional, post-transcriptional, and post-translational levels and whose mislocalization or dysregulation drives epithelial barrier disease and cancer phenotypes (PMID:26212084, PMID:34964704). Transcriptionally, CLDN2 is a direct target of the vitamin D receptor: VDR activates the CLDN2 promoter through a functional VDRE within the Cdx1 binding site, and intestinal epithelial-specific VDR deletion lowers claudin-2 expression in vivo (PMID:26212084). At the protein level, CLDN2 turnover proceeds through clathrin-mediated endocytosis coupled to autophagy, in which CLDN2 associates with clathrin, the AP2 subunits AP2A1 and AP2M1, and LC3; AP2M1 engages two YXXΦ tyrosine motifs of CLDN2 (residues 67–70 and 148–151) to route it to lysosomal degradation, and loss of AP2M1 or ATG7 raises CLDN2 levels and alters tight junction barrier function and intestinal permeability (PMID:34964704). CLDN2 mRNA is further regulated by METTL3-mediated, IGF2BP2-dependent m6A methylation that stabilizes the transcript, with this branch held in check by PRKN-driven K63 polyubiquitination of METTL3 (PMID:41925955), and by miR-194-3p, which binds the CLDN2 3′UTR to suppress its expression (PMID:41981457). In cancer, CLDN2 acts through distinct effector axes: it restrains osteosarcoma migration by upregulating afadin and suppressing Ras/Raf/MEK/ERK signaling (PMID:30349422), whereas in NSCLC it upregulates MRP2 to promote cisplatin resistance (PMID:41981457) and in colorectal cancer it supports proliferation, invasion, metastasis, and M2 macrophage polarization (PMID:41925955). Disease-linked alleles connect CLDN2 to pancreatitis susceptibility via acinar-cell mislocalization (PMID:23143602) and a gain-of-function missense variant to obstructive azoospermia (PMID:31320686).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 Medium

    Established that human genetic variation in CLDN2 contributes to disease by altering claudin-2 subcellular localization, linking the gene to barrier integrity in a clinical setting.

    Evidence Two-stage GWAS with replication and immunolocalization of claudin-2 in pancreatic acinar cells of risk-allele carriers

    PMID:23143602

    Open questions at the time
    • No functional reconstitution of how the risk allele drives mislocalization
    • Mechanism connecting mislocalization to acinar cell injury unresolved
  2. 2015 High

    Defined the transcriptional control of CLDN2 by identifying it as a direct VDR target, answering how an upstream signal sets claudin-2 levels in intestinal epithelium.

    Evidence Promoter-reporter assays, VDRE site-directed mutagenesis, and VDR knockout (whole-body and intestinal epithelial-specific) mice

    PMID:26212084

    Open questions at the time
    • Does not address whether VDR-driven CLDN2 changes alter barrier permeability functionally
    • Cofactors at the Cdx1/VDRE site not characterized
  3. 2018 Medium

    Placed CLDN2 upstream of an anti-migratory signaling axis, showing it can act as a signaling node rather than only a structural barrier component.

    Evidence Stable CLDN2 overexpression and knockout in bone cell lines, migration assays, afadin RNAi epistasis, and ERK pathway western blots

    PMID:30349422

    Open questions at the time
    • How CLDN2 mechanistically upregulates afadin is unknown
    • Single lab, single cancer context
  4. 2019 Low

    Connected a specific CLDN2 missense variant to a human reproductive barrier disease, implicating claudin-2 multimer assembly in the blood-epididymis barrier.

    Evidence Whole-exome sequencing, family co-segregation, and structural modeling of wild-type vs mutant claudin-2 multimers

    PMID:31320686

    Open questions at the time
    • Mechanism is computational only — no in vitro reconstitution or functional assay of the mutant
    • Direct effect on tight junction strand formation not measured experimentally
  5. 2019 Low

    Showed CLDN2 is ectopically induced in podocytes during active glomerular disease, expanding its disease relevance beyond epithelial tissues.

    Evidence Immunohistochemistry and immunoelectron microscopy on renal biopsies before and after remission

    PMID:31086291

    Open questions at the time
    • Observational/correlative with no experimental manipulation
    • Causal role of CLDN2 in pathological tight junction formation not tested
  6. 2021 High

    Resolved the post-translational degradation route of CLDN2, showing autophagy and clathrin-mediated endocytosis converge via AP2M1 recognition of YXXΦ motifs to control barrier function.

    Evidence Reciprocal Co-IP, membrane fractionation, YXXΦ motif mutagenesis, AP2M1 and ATG7 knockouts in vitro and in vivo, and ex vivo human colon

    PMID:34964704

    Open questions at the time
    • Upstream signals coupling starvation to CLDN2 endocytosis not fully defined
    • Whether other claudins use the same AP2M1 pathway unknown
  7. 2021 Medium

    Identified miR-194-3p as a direct post-transcriptional repressor of CLDN2 and tied CLDN2 to chemoresistance through MRP2 upregulation.

    Evidence Dual-luciferase 3′UTR reporter with mutants, miR-194-3p mimic/inhibitor, and cisplatin resistance assays in NSCLC cells

    PMID:41981457

    Open questions at the time
    • Mechanism by which CLDN2 upregulates MRP2 not defined
    • Single lab, NSCLC context only
  8. 2026 Medium

    Added an m6A-based layer of CLDN2 regulation, showing METTL3/IGF2BP2 stabilizes CLDN2 mRNA and that PRKN limits this axis, linking CLDN2 to colorectal tumor progression and immune modulation.

    Evidence RIP, luciferase, mRNA and protein stability assays, PRKN-METTL3 Co-IP, siRNA knockdown, and xenograft metastasis models

    PMID:41925955

    Open questions at the time
    • Direct molecular function of CLDN2 in driving invasion/M2 polarization not mechanistically dissected
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLDN2's pore-forming/barrier function at the protein level integrates with its multilayered regulation and its diverse cancer signaling outputs remains unresolved.
  • No structural or functional reconstitution of CLDN2 channel activity in the corpus
  • Whether transcriptional, m6A, miRNA, and degradation controls are coordinated is unknown
  • Mechanistic link between CLDN2 levels and downstream effectors (afadin, MRP2, macrophage polarization) is incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1500931 Cell-Cell communication 1 R-HSA-9612973 Autophagy 1
Partners
AP2A1AP2M1IGF2BP2LC3METTL3MLLT4
Complex memberships
tight junction

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 A CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells, and the homozygous/hemizygous CLDN2 genotype interacts with alcohol consumption to amplify pancreatitis risk, suggesting CLDN2 mislocalization in acinar cells contributes to disease susceptibility. Genome-wide association study with replication; immunolocalization of claudin-2 in pancreatic acinar cells from risk-allele carriers Nature genetics Medium 23143602
2015 The CLDN2 gene is a direct transcriptional target of the vitamin D receptor (VDR). VDR enhances CLDN2 promoter activity in a Cdx1 binding site-dependent manner, and a functional vitamin D response element (VDRE: 5′-AGATAACAAAGGTCA-3′) in the Cdx1 site of the CLDN2 promoter is required for VDR-mediated regulation. In vivo, intestinal epithelial-specific VDR deletion significantly decreased claudin-2 expression. Promoter-reporter assays, VDRE site-directed mutagenesis, VDR−/− whole-body and conditional intestinal epithelial VDR knockout (VDRδIEC) mice, cultured human intestinal epithelial cells Scientific reports High 26212084
2021 Autophagy-induced CLDN2 degradation proceeds through clathrin-mediated endocytosis: upon starvation, CLDN2 associates with clathrin, AP2 complex subunits (AP2A1 and AP2M1), and LC3, leading to lysosomal degradation. AP2M1 binds CLDN2 via two tyrosine motifs (YXXΦ) at residues 67–70 and 148–151. AP2M1 knockout or inhibition prevents autophagy-induced CLDN2 degradation and abolishes the associated enhancement of tight junction barrier function. ATG7 knockout cells showed increased baseline CLDN2 levels and increased intestinal permeability. Co-immunoprecipitation, membrane fractionation, pharmacological inhibition of clathrin-mediated endocytosis, site-directed mutagenesis of CLDN2 YXXΦ motifs, AP2M1 CRISPR knockout, ATG7 knockout (cells and in vivo mouse model), ex vivo human colon experiments Autophagy High 34964704
2018 CLDN2 overexpression in osteosarcoma cells significantly inhibits cell migration. This effect is mediated through upregulation of afadin, which in turn suppresses the Ras/Raf/MEK/ERK pathway. RNAi silencing of afadin in CLDN2-overexpressing cells restored cell motility and ERK pathway activation, placing CLDN2 upstream of afadin in this anti-metastatic signaling axis. Stable CLDN2 overexpression in OS cell line, CLDN2 knockout in osteoblast line, transwell and wound-healing migration assays, RNAi knockdown of afadin, western blot for ERK pathway activation Cancer cell international Medium 30349422
2019 A gain-of-function missense variant in CLDN2 (c.481G>C; p.Gly161Arg) co-segregates with obstructive azoospermia in a multiplex family. Structural modeling showed that this single residue change alters dimeric and tetrameric claudin-2 strand formation, predicted to disrupt tight junctions in the blood-epididymis barrier. Whole-exome sequencing, family-based co-segregation analysis, protein structural modeling of wild-type vs. mutant claudin-2 multimeric arrangements Journal of human genetics Low 31320686
2021 miR-194-3p directly binds to two conserved sites (nt 358–365 and 1232–1238) in the CLDN2 3′ UTR, suppressing CLDN2 expression via mRNA degradation and translational inhibition. CLDN2 upregulates multidrug resistance-associated protein 2 (MRP2), thereby promoting cisplatin resistance in NSCLC cells. The natural compound arteannuin B exerts antitumor effects by upregulating miR-194-3p, which suppresses CLDN2. Transcriptomic profiling, dual-luciferase reporter assay with CLDN2 3′ UTR mutants, functional cell proliferation and cisplatin resistance assays, miR-194-3p mimic/inhibitor transfection Cancer medicine Medium 41981457
2026 METTL3 promotes m6A methylation of CLDN2 mRNA in an IGF2BP2-dependent manner, stabilizing CLDN2 mRNA and increasing CLDN2 protein levels in colorectal cancer cells. PRKN (Parkin) promotes K63-linked polyubiquitination and degradation of METTL3 protein, thereby indirectly reducing CLDN2 levels. CLDN2 depletion suppresses CRC cell proliferation, invasion, migration, and M2 macrophage polarization, and inhibits tumor growth and lung metastasis in xenograft models. RNA immunoprecipitation (RIP), luciferase assays, co-immunoprecipitation (PRKN-METTL3 interaction), mRNA stability assay (actinomycin D), protein stability assay (cycloheximide), METTL3/CLDN2 siRNA knockdown, in vivo xenograft tumor and metastasis models Cell biology and toxicology Medium 41925955
2019 CLDN2 is ectopically expressed in podocytes in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) before remission, where it localizes along newly formed tight junctions. CLDN2 expression level correlates with active disease and decreases upon remission, suggesting CLDN2 participates in the formation of pathological tight junction-like structures in podocytes. Immunohistochemistry and immunoelectron microscopy on renal biopsy specimens from pediatric NS patients (MCD, FSGS, IgA nephritis) before and after remission Pediatric research Low 31086291

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nature genetics 250 23143602
2015 Tight junction CLDN2 gene is a direct target of the vitamin D receptor. Scientific reports 109 26212084
2014 Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut 85 25253127
2021 AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability. Autophagy 78 34964704
2007 Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer. Molecular cancer research : MCR 66 17314274
2013 Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ open 43 24002981
2018 CLDN2 inhibits the metastasis of osteosarcoma cells via down-regulating the afadin/ERK signaling pathway. Cancer cell international 31 30349422
2021 LncRNA NKILA knockdown promotes cell viability and represses cell apoptosis, autophagy and inflammation in lipopolysaccharide-induced sepsis model by regulating miR-140-5p/CLDN2 axis. Biochemical and biophysical research communications 28 33932903
2016 Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis. PloS one 27 26820620
2019 Identification of a missense variant in CLDN2 in obstructive azoospermia. Journal of human genetics 18 31320686
2016 Association Analysis of PRSS1-PRSS2 and CLDN2-MORC4 Variants in Nonalcoholic Chronic Pancreatitis Using Tropical Calcific Pancreatitis as Model. Pancreas 13 26784911
2020 miR-331 inhibits CLDN2 expression and may alleviate the vascular endothelial injury induced by sepsis. Experimental and therapeutic medicine 7 32742369
2024 Duck circovirus regulates the expression of duck CLDN2 protein by activating the MAPK-ERK pathway to affect its adhesion and infection. Journal of virology 3 39345142
2022 Mutations in CLDN2 Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada. Canadian journal of kidney health and disease 3 35615069
2024 A retinoid analogue, TTNPB, promotes clonal expansion of human pluripotent stem cells by upregulating CLDN2 and HoxA1. Communications biology 1 38365890
2019 Ectopic expression of CLDN2 in podocytes is associated with childhood onset nephrotic syndrome. Pediatric research 1 31086291
2026 The PRKN/METTL3/CLDN2 axis promotes colorectal cancer development through epigenetic mechanisms. Cell biology and toxicology 0 41925955
2026 Arteannuin B Inhibits NSCLC Cells via Regulating miR-194-3p/CLDN2 Axis. Cancer medicine 0 41981457

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