Substratum stiffness regulates Erk signaling dynamics through receptor-level control

Area of Science:

• Cell Biology
• Biophysics
• Mechanobiology

Background:

• The Epidermal Growth Factor Receptor/Extracellular signal-regulated kinase (EGFR/Erk) pathway is crucial for cell signaling, responding to both external ligands and mechanical cues.
• While ligand stimulation effects on Erk dynamics are known, the impact of microenvironmental mechanical properties on these dynamics remains unclear.

Purpose of the Study:

• To investigate how substratum stiffness, a key mechanical property, affects Erk signaling dynamics in mammary epithelial cells.
• To elucidate the mechanisms by which mechanical cues modulate Erk pathway activity.

Main Methods:

• Utilized mammary epithelial cells cultured on substrata of varying stiffness.
• Employed optogenetic tools to manipulate signaling nodes within the EGFR/Erk pathway.
• Quantified Erk signaling activity, EGFR expression, and epidermal growth factor (EGF) binding dynamics.

Main Results:

• Soft microenvironments significantly attenuate Erk signaling, both at basal levels and upon EGF stimulation.
• Substratum stiffness does not substantially affect intracellular signal transmission within the Erk pathway.
• Soft environments lead to decreased EGFR expression and altered EGF binding at the cell membrane.

Conclusions:

• The mechanical microenvironment, through substratum stiffness, tunes Erk signaling dynamics primarily by modulating EGFR expression and EGF-receptor interactions.
• These findings highlight the integration of mechanical and chemical signals in regulating conserved pathways involved in tissue development and disease.