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

Abstract

Finigan JH, Vasu VT, Thaikoottathil JV, Mishra R, Shatat MA, Mason RJ, Kern JA. HER2 activation results in ␤-catenindependent changes in pulmonary epithelial permeability. Am J Physiol Lung Cell Mol Physiol 308: L199 -L207, 2015. First published October 17, 2014; doi:10.1152/ajplung.00237.2014.-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.human epidermal growth factor receptor-2; neuregulin-1; receptor tyrosine kinase; ␤-catenin; epithelial cell; permeability; adherens junction; cell adhesion THE PULMONARY EPITHELIUM SERVES as the interface for the lung with the outside world and is responsible for numerous critical functions central to lung function. In the airways and alveoli, epithelial cells serve as a physical barrier against toxins and microorganisms and regulate solute and fluid flux. Numerous lung diseases are marked by injury to the pulmonary epithelium, leading to disruption of the epithelial barrier, and a rapid and efficient restoration of the epithelial barrier is essential to repair of the damaged lung (10, 46). However, understanding of the mechanisms that regulate cell-cell adhesion and epithelial barrier function in the lung is incomplete.The epithelial cell barrier consists of epithelial cells joined by a belt-like apical junctional complex (AJC). The AJC is responsible for lateral adhesion between cells and acts as an obstacle to macromolecule diffusion through its major domains, tight junctions (TJ) and adherens junctions (AJ) (15,29). The TJ acts as a gate, regulating solute flux, and a fence, preventing diffusion of proteins and lipids between the outer leaflet of the apical and basolateral plasma membrane domains.The AJ is essential for cell-cell adhesion. The AJ protein ␤-catenin connects the intracellular actin cytoskeleton to the transmembrane protein epithelial (E)-cadherin. E-cadherin, in turn, bridges extracellularly in trans with an E-cadherin molecule on an adjacent epithelial cell to establish cell-cell adhesion (22, 49). Thus ␤-catenin is a critical participant in maintaining cell-cell adhesion and ...

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

“…The analysis of phenotype transit and signaling molecular indicated that HER2 may function through upregulation of β‐catenin and inhibition of SMAD2/3 complex activation. The functional connection among HER2, β‐catenin, and SMAD3 was supported with the evidence that HER2 and β‐catenin are physically associated . Immunoprecipitation of HER2 in normal and transformed epithelial cells was coimmunoprecipitated with the cadherin‐catenin complex, revealing a HER2 and β‐catenin in association with the basal condition .…”

“…Immunoprecipitation of HER2 in normal and transformed epithelial cells was coimmunoprecipitated with the cadherin‐catenin complex, revealing a HER2 and β‐catenin in association with the basal condition . The connection between HER2 and SMAD3 independent of TGF‐β receptor might be regulated through β‐catenin/Smad3 colocalization …”

Cigarette Smoke Induces Human Epidermal Receptor 2–Dependent Changes in Epithelial Permeability

“…HER2 has no known ligand, yet partners with other HER family members. For example, we have previously identified that HER2 dimerizes with HER3 after HER3 binding with the ligand neuregulin (NRG)-1, which leads to HER2-dependent increases in pulmonary epithelial permeability (11,12), and the NRG-1-HER2/3 signaling cascade participates in the pathogenesis of acute lung injury and the acute respiratory distress syndrome (7,8,11). Although HER2 is known to participate in epithelial barrier dysfunction in air-liquid interface (ALI), it has been unstudied in models of CS exposure.…”

“…Generally, HER receptor activation occurs rapidly after ligand binding (11,12). Given this, we next sought to determine if transient, acute CS induced activation of HER2 in cultured pulmonary epithelial cells.…”

“…HER2 is known to modulate epithelial barrier function (11,12), although whether it participates in epithelial barrier dysfunction after CS is unknown. To address this, NuLi-1 cells transfected with HER2 shRNA were grown to confluence (>800 mV) at ALI, exposed to CS, and resistance was measured over 24 hours ( Figure 6A).…”