Substratum stiffness regulates Erk signaling dynamics through receptor-level control

Payam E. Farahani, Sandra B. Lemke, Elliot Dine, Giselle Uribe, Jared E. Toettcher, Celeste M. Nelson

Abstract

The EGFR/Erk pathway is triggered by extracellular ligand stimulation, leading to stimulus-dependent dynamics of pathway activity. Although mechanical properties of the microenvironment also affect Erk activity, their effects on Erk signaling dynamics are poorly understood. Here, we characterize how the stiffness of the underlying substratum affects Erk signaling dynamics in mammary epithelial cells. We find that soft microenvironments attenuate Erk signaling, both at steady state and in response to epidermal growth factor (EGF) stimulation. Optogenetic manipulation at multiple signaling nodes reveals that intracellular signal transmission is largely unaffected by substratum stiffness. Instead, we find that soft microenvironments decrease EGF receptor (EGFR) expression and alter the amount and spatial distribution of EGF binding at cell membranes. Our data demonstrate that the mechanical microenvironment tunes Erk signaling dynamics via receptor-ligand interactions, underscoring how multiple microenvironmental signals are jointly processed through a highly conserved pathway that regulates tissue development, homeostasis, and disease progression.

Original languageEnglish (US)
Article number110181
JournalCell Reports
Volume37
Issue number13
DOIs
StatePublished - Dec 28 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • MAP kinase
  • morphodynamics
  • receptor tyrosine kinase
  • signaling dynamics
  • tissue mechanics

Fingerprint

Dive into the research topics of 'Substratum stiffness regulates Erk signaling dynamics through receptor-level control'. Together they form a unique fingerprint.

Cite this