Finigan James H, Vasu Vihas T, Thaikoottathil Jyoti V, Mishra Rangnath, Shatat Mohammad A, Mason Robert J, Kern Jeffrey A
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
Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado;
Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L199-207. doi: 10.1152/ajplung.00237.2014. Epub 2014 Oct 17.
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.
受体酪氨酸激酶人类表皮生长因子受体2（HER2）已知可调节肺上皮屏障功能；然而，这种作用背后的机制仍不明晰。我们推测HER2信号传导通过与黏附连接（AJ）蛋白β-连环蛋白相互作用改变上皮屏障，导致AJ解体。在静止的肺上皮细胞中，HER2和β-连环蛋白沿细胞间外侧连接共定位。配体神经调节蛋白-1激活HER2与β-连环蛋白的酪氨酸磷酸化、β-连环蛋白与E-钙黏蛋白的解离以及E-钙黏蛋白介导的细胞黏附降低有关。所有这些作用均被HER2抑制剂拉帕替尼阻断。使用短发夹RNA（shRNA）敲低β-连环蛋白可显著减弱神经调节蛋白-1在体外诱导的肺上皮电阻降低。我们的数据表明，HER2与β-连环蛋白相互作用，导致AJ解体、细胞间黏附降低以及肺上皮屏障破坏。
