HER2 activation results in ?-catenin-dependent changes in pulmonary epithelial permeability.
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 ?-catenin, leading to dissolution of the ... AJ. In quiescent pulmonary epithelial cells, HER2 and ?-catenin colocalized along the lateral intercellular junction. HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of ?-catenin, dissociation of ?-catenin from E-cadherin, and decreased E-cadherin-mediated cell adhesion. All effects were blocked with the HER2 inhibitor lapatinib. ?-Catenin knockdown using shRNA significantly attenuated neuregulin-1-induced decreases in pulmonary epithelial resistance in vitro. Our data indicate that HER2 interacts with ?-catenin, leading to dissolution of the AJ, decreased cell-cell adhesion, and disruption of the pulmonary epithelial barrier.
Mesh Terms:
Adherens Junctions, Cell Adhesion, Cell Line, Electric Impedance, Enzyme Activation, Humans, Lapatinib, Lung, Neuregulin-1, Permeability, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, RNA Interference, RNA, Small Interfering, Receptor, ErbB-2, Respiratory Mucosa, Signal Transduction, Tight Junctions, beta Catenin
Adherens Junctions, Cell Adhesion, Cell Line, Electric Impedance, Enzyme Activation, Humans, Lapatinib, Lung, Neuregulin-1, Permeability, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, RNA Interference, RNA, Small Interfering, Receptor, ErbB-2, Respiratory Mucosa, Signal Transduction, Tight Junctions, beta Catenin
Am J Physiol Lung Cell Mol Physiol
Date: Jan. 15, 2015
PubMed ID: 25326580
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