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HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability

Finigan JH, Vasu VT, Thaikoottathil JV, Mishra R, Shatat MA, Mason RJ, Kern JA. HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability. Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L199-207. doi: 10.1152/ajplung.00237.2014. Epub 2014 Oct 17.

Abstract

The receptor tyrosine kinase human epidermal growth factor receptor-2 (HER2) is known to regulate pulmonary epithelial barrier function; however, the mechanisms behind this effect remain unidentified. We hypothesized that HER2 signaling alters the epithelial barrier through an interaction with the adherens junction (AJ) protein β-catenin, leading to dissolution of the AJ. In quiescent pulmonary epithelial cells, HER2 and β-catenin colocalized along the lateral intercellular junction. HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of β-catenin, dissociation of β-catenin from E-cadherin, and decreased E-cadherin-mediated cell adhesion. All effects were blocked with the HER2 inhibitor lapatinib.
β-Catenin knockdown using shRNA significantly attenuated neuregulin-1-induced decreases in pulmonary epithelial resistance in vitro. Our data indicate that HER2 interacts with β-catenin, leading to dissolution of the AJ, decreased cell-cell adhesion, and disruption of the pulmonary epithelial barrier.
Keywords: adherens junction; cell adhesion; epithelial cell; human epidermal growth factor receptor-2; neuregulin-1; permeability; receptor tyrosine kinase; β-catenin.

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