δ-Catenin dysregulation in cancer: interactions with E-cadherin and beyond

Abstract

Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120(ctn) subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to delta-catenin/NPRAP/neurojungin (CTNND2) and p120(ctn) (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120(ctn) further highlighted possibilities of intervening between interactions of p120(ctn) subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120(ctn) expression or alteration of its subcellular distribution. On the other hand, delta-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up-regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120(ctn) (CTNND1) gene amplification in lung cancer. One mechanism by which delta-catenin and p120(ctn) may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of delta-catenin overexpression in lung cancer. Unexpectedly, the authors observed that delta-catenin promotes malignant phenotypes of non-small cell lung cancer by non-competitive binding to E-cadherin with p120(ctn) in the cytoplasm. Looking towards the future, the understanding of delta-catenin and p120(ctn) with and beyond their localization at the cell-cell junction should provide further insight into their roles in cancer pathogenesis.

Figure 1. δ-Catenin and its potential interactions with E-cadherin in cancer

A. Schematic illustration of δ-catenin in comparison to other armadillo-domain containing proteins. While β-catenin and γ-catenin display 13 armadillo repeating units and Adenomatous Polyposis Coli (APC) shows 6 such repeating units, δ-catenin, p120^ctn, ARVCF, and p0071 carry 10 repeating units. B. Immunofluorescent light microscopy showing partial co-distribution of δ-catenin with E-cadherin in lung cancer cell line NCI-H1299. a. Anti-E-cadherin. b. Hoechst staining to show nuclear morphology. c. EGFP-δ-catenin. d. Merged image of a, b, and c. Stable NCI-H1299 cells expressing EGFP-δ-catenin were transiently transfected with human E-cadherin plasmid and immunostained using mouse anti-E-cadherin. Asterisks indicate the cell transfected with E-cadherin. Arrows point to the cell-cell junctions that can be observed in some cells. Note: ectopic expressed E-cadherin fails to localize to plasma membrane and remains in the cytoplasm. Bar: 10 μm.