RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial–Mesenchymal Transition, Migration, and Invasion of Lung Alveolar Epithelial Cells
2019
Previously, we demonstrated that growth arrest-specific protein 6 (
Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced
epithelial–mesenchymal transition(EMT) in lung epithelial cells.
Hepatocyte growth factor(HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether
Gas6signaling can induce the production of HGF and
c-Metin lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the
RhoA/Rho kinase pathway, using either a
RhoA-targeted
small interfering RNA(siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The
c-Metantagonist PHA-665752 also blocked the anti-EMT effects associated with
Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the
Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the
RhoA-dependent production of HGF and
c-Metmediated the
Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus,
Gas6/Axl and Mer/
RhoAsignaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and
c-Met.
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