Details for: CLDN18

Gene ID: 51208

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CLDN18

Ensembl ID: ENSG00000066405

Description: claudin 18

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • ependymal cell CL0000065
    CSI 15.39
    rCSI 31.23%
    PRS 94.82
  • mucous neck cell CL0000651
    CSI 11.53
    rCSI 16.62%
    PRS 99.11
  • foveolar cell of stomach CL0002179
    CSI 9.96
    rCSI 21.21%
    PRS 99.13
  • epithelial cell of lung CL0000082
    CSI 5.14
    rCSI 4.26%
    PRS 99.6
  • intestine goblet cell CL0019031
    CSI 4.78
    rCSI 4.24%
    PRS 98.76
  • goblet cell CL0000160
    CSI 4.39
    rCSI 4.15%
    PRS 98.94
  • lung secretory cell CL1000272
    CSI 4.23
    rCSI 10.46%
    PRS 99.56
  • enteroendocrine cell CL0000164
    CSI 4.07
    rCSI 5.56%
    PRS 98.22
  • pulmonary alveolar type 2 cell CL0002063
    CSI 4.01
    rCSI 6.23%
    PRS 99.05
  • epithelial cell of lower respiratory tract CL0002632
    CSI 3.83
    rCSI 2.97%
    PRS 99.63
  • stem cell CL0000034
    CSI 3.69
    rCSI 3.56%
    PRS 98.96
  • paneth cell CL0000510
    CSI 2.05
    rCSI 3.02%
    PRS 99.55
  • peptic cell CL0000155
    CSI 1.61
    rCSI 15.83%
    PRS 98.83
  • pulmonary alveolar type 1 cell CL0002062
    CSI 1.59
    rCSI 9.19%
    PRS 98.5
  • parietal cell CL0000162
    CSI 1.25
    rCSI 10.74%
    PRS 98.88
  • P/D1 enteroendocrine cell CL0002268
    CSI 0.97
    rCSI 5.26%
    PRS 98.74

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CLDN18](/details-gene/51208) encodes Claudin-18, a tetraspanin transmembrane protein that is an essential component of tight junctions. It plays a critical role in maintaining cell polarity and regulating paracellular permeability, establishing barriers in epithelial cell sheets. Research has identified two splice variants, CLDN18.1 and CLDN18.2, with CLDN18.1 being specifically expressed in the lung and CLDN18.2 being highly restricted to the gastric mucosa ([Link](https://doi.org/10.1128/mcb.21.21.7380-7390.2001)). Its highly specific expression profile and its aberrant expression in various cancers have made the CLDN18.2 isoform a significant target for cancer immunotherapy ([Link](https://doi.org/10.1158/1078-0432.ccr-08-1547)). ## Cellular Roles and Expression Landscape The expression of [CLDN18](/details-gene/51208) is highly specialized, primarily confined to specific epithelial and secretory cell populations. **Overall**, the gene shows the highest significance in cells responsible for forming tight barriers or producing secretions. Its top expression is observed in [ependymal cells](/details-cell/CL0000065) (CSI: 15.39), which line the ventricles of the brain, suggesting a role in the blood-cerebrospinal fluid barrier. Functionally, its expression profile highlights two major organ systems: * **Gastrointestinal Tract:** [CLDN18](/details-gene/51208) is a defining marker for several gastric cell types, including [mucous neck cells](/details-cell/CL0000651) (CSI: 11.53) and [foveolar cells of the stomach](/details-cell/CL0002179) (CSI: 9.96). Its significance extends to other secretory and absorptive cells of the gut, such as [intestine goblet cells](/details-cell/CL0019031), [enteroendocrine cells](/details-cell/CL0000164), and [paneth cells](/details-cell/CL0000510). This pattern underscores its fundamental role in maintaining the gastric mucosal barrier. * **Respiratory System:** The gene is also highly significant in various lung epithelial cells, including the general [epithelial cell of lung](/details-cell/CL0000082) (CSI: 5.14) and more specialized cells like [pulmonary alveolar type 2 cells](/details-cell/CL0002063) and [pulmonary alveolar type 1 cells](/details-cell/CL0002062). This expression is consistent with studies demonstrating that its deficiency leads to alveolar barrier dysfunction ([Link](https://doi.org/10.1165/rcmb.2013-0456oc)). The highly restricted expression to these epithelial lineages suggests that [CLDN18](/details-gene/51208) is not a general housekeeping gene but rather a specialized structural protein crucial for organ-specific barrier function. ## Pathways and Molecular Function The functional annotations for [CLDN18](/details-gene/51208) are strongly centered on cell-cell adhesion and junctional organization. As a structural molecule ([GO:0005198](https://www.ebi.ac.uk/QuickGO/term/GO:0005198)), its primary role is within the [bicellular tight junction](/details-cell/GO:0005923). This is reflected in its involvement in processes such as [Bicellular tight junction assembly (GO:0070830)](https://www.ebi.ac.uk/QuickGO/term/GO:0070830) and [Tight junction organization (GO:0120193)](https://www.ebi.ac.uk/QuickGO/term/GO:0120193). Its function is further detailed by its participation in Reactome pathways like [Tight junction interactions (R-HSA-420029)](https://reactome.org/content/detail/R-HSA-420029) and [Cell-cell junction organization (R-HSA-421270)](https://reactome.org/content/detail/R-HSA-421270). Beyond its structural role, [CLDN18](/details-gene/51208) is implicated in developmental processes consistent with its expression profile, including [Digestive tract development (GO:0048565)](https://www.ebi.ac.uk/QuickGO/term/GO:0048565) and [Lung alveolus development (GO:0048286)](https://www.ebi.ac.uk/QuickGO/term/GO:0048286). This suggests that the gene is not only important for maintaining adult tissue barriers but is also essential for their proper formation during organogenesis. ## Research Directions The highly restricted expression of [CLDN18](/details-gene/51208), particularly the CLDN18.2 isoform, in healthy tissues versus its aberrant expression in multiple cancers, provides a unique therapeutic window. Future research should focus on the mechanisms driving this differential expression and the functional consequences in a pathological context. **Proposed Hypotheses:** 1. Aberrant expression of the CLDN18.2 isoform in non-gastric cancers (e.g., pancreatic, esophageal) is driven by epigenetic reprogramming or transcription factor dysregulation, leading to a breakdown of normal cell-cell adhesion that facilitates epithelial-mesenchymal transition (EMT) and metastasis. 2. In lung diseases such as Acute Respiratory Distress Syndrome (ARDS), inflammatory cytokines specifically downregulate [CLDN18](/details-gene/51208) expression in [pulmonary alveolar type 2 cells](/details-cell/CL0002063), compromising the alveolar-capillary barrier and contributing to pulmonary edema. **Experimental Approach:** To test the first hypothesis, one could utilize pancreatic ductal adenocarcinoma (PDAC) cell lines that do not normally express CLDN18.2. Ectopic expression of CLDN18.2 could be induced, followed by RNA-sequencing to identify changes in EMT-related gene signatures. Functional consequences could be assessed using in vitro models, such as Transwell migration assays to measure changes in cell invasion and immunofluorescence to observe the disruption of other junctional proteins like E-cadherin and ZO-1. **Therapeutic Potential:** [CLDN18](/details-gene/51208) (specifically the CLDN18.2 isoform) represents an outstanding therapeutic target. Its near-absent expression in most healthy tissues, combined with its high expression on the surface of cancer cells (gastric, pancreatic, esophageal, and others), makes it an ideal candidate for targeted therapies ([Link](https://doi.org/10.1158/1078-0432.ccr-08-1547)). The therapeutic strategy would involve targeted cell killing. It is already being pursued clinically with modalities such as monoclonal antibodies (e.g., zolbetuximab), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T cell therapies, which aim to selectively eliminate tumor cells expressing this protein while sparing healthy tissue.

Genular Protein ID: 2163846225

Symbol: CLD18_HUMAN

Name: Claudin-18

UniProtKB Accession Codes:

P56856 A5PL21 Q96PH4

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 2 ExpressionAtlas 1 GO 22 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 2 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11585919

Title: Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing.

PubMed ID: 11585919

DOI: 10.1128/mcb.21.21.7380-7390.2001

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 19047087

Title: Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development.

PubMed ID: 19047087

DOI: 10.1158/1078-0432.ccr-08-1547

PubMed ID: 19706394

Title: Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium.

PubMed ID: 19706394

DOI: 10.1073/pnas.0907724106

PubMed ID: 24787463

Title: Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice.

PubMed ID: 24787463

DOI: 10.1165/rcmb.2013-0456oc

Sequence Information:

  • Length: 261
  • Mass: 27856
  • Checksum: 4362B590D3C2B387
  • Sequence:
    • MSTTTCQVVA FLLSILGLAG CIAATGMDMW STQDLYDNPV TSVFQYEGLW RSCVRQSSGF 
TECRPYFTIL GLPAMLQAVR ALMIVGIVLG AIGLLVSIFA LKCIRIGSME DSAKANMTLT 
SGIMFIVSGL CAIAGVSVFA NMLVTNFWMS TANMYTGMGG MVQTVQTRYT FGAALFVGWV 
AGGLTLIGGV MMCIACRGLA PEETNYKAVS YHASGHSVAY KPGGFKASTG FGSNTKNKKI 
YDGGARTEDE VQSYPSKHDY V