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RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial-Mesenchymal Transition, Migration, and

Jihye Jung1,2, Kyungwon Yang3, Hee-Ja Kim4

  • 1Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Korea. wowow0523@naver.com.

Biomolecules
|October 9, 2019
PubMed

Insights

Growth arrest-specific protein 6 (Gas6) signaling inhibits lung epithelial cell changes by inducing hepatocyte growth factor (HGF) and c-Met. This pathway, involving RhoA, is crucial for maintaining alveolar epithelial homeostasis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pulmonary Medicine

Background:

  • Growth arrest-specific protein 6 (Gas6) and its receptors Axl/Mer inhibit transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) in lung cells.
  • Hepatocyte growth factor (HGF) also suppresses TGF-β1-induced EMT markers.

Purpose of the Study:

  • To investigate if Gas6 signaling induces HGF and c-Met production in lung alveolar epithelial cells.
  • To determine if this induction mediates the inhibition of EMT, migration, and invasion.
  • To elucidate the role of the RhoA/Rho kinase pathway in Gas6-mediated effects.

Main Methods:

  • Utilized RhoA-targeted small interfering RNA (siRNA) and Rho kinase inhibitor Y27362 to block the RhoA/Rho kinase pathway.
  • Employed c-Met antagonist PHA-665752 to assess the role of c-Met.
  • Examined effects on TGF-β1-induced EMT markers, migration, and invasion in LA-4 cells and primary alveolar type II (AT II) epithelial cells.

Main Results:

  • Inhibition of the RhoA/Rho kinase pathway prevented Gas6's anti-EMT effects.
  • The c-Met antagonist PHA-665752 blocked Gas6's anti-EMT effects.
  • Gas6-mediated inhibition of TGF-β1-induced migration and invasion was prevented by Y27362 and PHA-665752.
  • Data indicated RhoA-dependent production of HGF and c-Met mediates Gas6's inhibition of EMT, migration, and invasion.

Conclusions:

  • Gas6 signaling inhibits EMT, migration, and invasion in lung alveolar epithelial cells via RhoA-dependent HGF and c-Met production.
  • Gas6/Axl and Mer/RhoA signaling pathways, through HGF and c-Met, are essential for maintaining alveolar epithelial homeostasis.
Keywords:
Hepatocyte growth factorc-Metepithelial-mesenchymal transitiongrowth arrest-specific protein 6lung epithelial cells

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