HER2 activation results in β-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 a...

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Veröffentlicht in:American journal of physiology. Lung cellular and molecular physiology 2015-01, Vol.308 (2), p.L199-L207
Hauptverfasser: Finigan, James H, Vasu, Vihas T, Thaikoottathil, Jyoti V, Mishra, Rangnath, Shatat, Mohammad A, Mason, Robert J, Kern, Jeffrey A
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Sprache:eng
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Zusammenfassung: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.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00237.2014