title: HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; Division of Oncology, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado FiniganJ@NJHealth.org.
authors.forename: James H
authors.initials: JH
authors.lastname: Finigan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado;
authors.forename: Vihas T
authors.initials: VT
authors.lastname: Vasu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado;
authors.forename: Jyoti V
authors.initials: JV
authors.lastname: Thaikoottathil
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado;
authors.forename: Rangnath
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; and.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Shatat
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; Division of Oncology, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kern
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D017097:Electric Impedance; D004789:Enzyme Activation; D006801:Humans; D000077341:Lapatinib; D008168:Lung / Q000502:physiology; D020890:Neuregulin-1 / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000077341:Lapatinib; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C508053:ERBB2 protein, human
keywords: adherens junction; cell adhesion; epithelial cell; human epidermal growth factor receptor-2; neuregulin-1; permeability; receptor tyrosine kinase; β-catenin