Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells.

Singh AB, Harris RC
J Biol Chem. 2004 279 (5): 3543-52

PMID: 14593119 · DOI:10.1074/jbc.M308682200

Tight junctions (TJs) are the most apical cell-cell junctions, and claudins, the recently identified TJ proteins, are critical for maintaining cell-cell adhesion in epithelial cell sheets. Based on their in vivo distribution and the results of overexpression studies, certain claudins, including claudin-1 and -4, are postulated to increase, whereas other claudins, especially claudin-2, are postulated to decrease the overall transcellular resistance. The overall ratio among claudins expressed in a cell/tissue has been hypothesized to define the complexity of TJs. Disruption of the TJs contributes to various human diseases, and a correlation between reduction of TJ function and tumor dedifferentiation has been postulated. The epidermal growth factor (EGF) receptor (EGFR) is overexpressed in a wide spectrum of epithelial cancers, and its expression correlates with a more metastatic cancer phenotype. However, normal functioning of EGFR is essential for normal epithelial cell proliferation and differentiation. The role of EGFR-dependent signaling in the development and maintenance of epithelial TJ integrity has not been studied in detail. This study demonstrates that, in polarized Madin-Darby canine kidney II cells, EGF-induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1, -3, and -4. Accompanying these EGF-induced changes in claudin expression was a 3-fold increase in transepithelial resistance, a functional measure of TJs. In contrast, there were no alterations in protein expression and/or intracellular localization of other TJ-related proteins (ZO-1 and occludin) or adherens junction-associated proteins (E-cadherin and beta-catenin), suggesting that EGF regulates TJ function through selective and differential regulation of claudins.

MeSH Terms (31)

Acetylcysteine Adherens Junctions Animals Blotting, Northern Bromodeoxyuridine Cell Adhesion Cell Differentiation Cell Division Cell Line Claudin-1 Claudin-3 Claudin-4 Claudins Cycloheximide Detergents Dogs Epithelium ErbB Receptors Gene Expression Regulation Hepatocyte Growth Factor Immunoblotting Kidney Membrane Proteins Microscopy, Fluorescence Neoplasms Octoxynol Phenotype Protein Synthesis Inhibitors Signal Transduction Tight Junctions Time Factors

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