Abstract
SUMMARYThe 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.
Highlights
In growth factor signaling, extracellular ligands bind to receptor tyrosine kinases at the cell surface, initiating a cascade of signaling events to phosphorylate the terminal kinase Erk and trigger downstream cellular processes including growth, proliferation, and migration
It is still unknown how single-cell Erk dynamics vary as a function of substratum stiffness and which mechanically regulated steps control the response of growth factor signaling through Erk
Our findings reveal how substratum stiffness tunes signal transmission along the EGF receptor (EGFR)/Erk pathway, implicating ligand-receptor interactions as a key signaling step accentuated by stiff microenvironments
Summary
Extracellular ligands bind to receptor tyrosine kinases at the cell surface, initiating a cascade of signaling events to phosphorylate the terminal kinase Erk and trigger downstream cellular processes including growth, proliferation, and migration. Live-cell studies have shown that Erk activity is regulated by cell density (Aoki et al, 2013), integrin expression (Hiratsuka et al, 2020), and protrusive forces (Yang et al, 2018). Despite these advances, it is still unknown how single-cell Erk dynamics vary as a function of substratum stiffness and which mechanically regulated steps control the response of growth factor signaling through Erk
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