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ECM stiffness regulates lung fibroblast survival through RasGRF1-dependent signaling.

Elizabeth Monaghan-Benson1, Julien Aureille2, Christophe Guilluy1

  • 1Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.

The Journal of Biological Chemistry
|January 10, 2025
PubMed
Summary

Matrix stiffness enhances lung fibroblast survival via RasGRF1 activation. This pathway involves AKT and ERK signaling, affecting FOXO3a and Bim to regulate cell survival.

Keywords:
AKTBcl-2 familyERKFOXORasapoptosisextracellular matrixmechanotransductionsignaling

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Area of Science:

  • Cell Biology
  • Biophysics
  • Mechanobiology

Background:

  • Cellular behavior is influenced by mechanical signals, including extracellular matrix (ECM) stiffness.
  • Lung fibroblasts' survival is modulated by their surrounding mechanical environment.

Purpose of the Study:

  • To investigate the molecular mechanisms by which ECM stiffness affects lung fibroblast survival.
  • To identify key signaling pathways and proteins involved in mechanotransduction.

Main Methods:

  • Utilized lung fibroblasts cultured on substrates of varying stiffness.
  • Employed biochemical assays to measure Ras activity and Western blotting for signaling pathway analysis.
  • Used RNA interference (RNAi) and pharmacological inhibitors to probe specific signaling components (RasGRF1, AKT, ERK, FOXO3a, Bim).

Main Results:

  • Enhanced survival of lung fibroblasts on stiff substrates correlated with increased Ras activity, mediated by RasGRF1.
  • Increased Ras activity activated both AKT and ERK signaling pathways.
  • Inhibition of AKT or ERK signaling reduced survival on stiff substrates.
  • FOXO3a activity was crucial for cell death on soft substrates and its downregulation on stiff substrates led to Bim degradation.
  • Depletion of Bim enhanced fibroblast survival on soft substrates.

Conclusions:

  • ECM stiffness activates a RasGRF1/Ras signaling cascade in lung fibroblasts.
  • This cascade modulates AKT and ERK pathways, influencing the activity of FOXO3a and the expression of Bim.
  • The RasGRF1-AKT-ERK-FOXO3a-Bim axis is a critical determinant of cell survival in response to matrix stiffness.