Substratum stiffness regulates Erk signaling dynamics through receptor-level control. Author Payam Farahani, Sandra Lemke, Elliot Dine, Giselle Uribe, Jared Toettcher, Celeste Nelson Publication Year 2021 Type Journal Article 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. Keywords Extracellular Matrix, Humans, Signal Transduction, Phosphorylation, Female, Cells, Cultured, Cell Movement, Extracellular Signal-Regulated MAP Kinases, ErbB Receptors, Mammary Glands, Human, Cellular Microenvironment Journal Cell Rep Volume 37 Issue 13 Pages 110181 Date Published 2021 Dec 28 ISSN Number 2211-1247 DOI 10.1016/j.celrep.2021.110181 Alternate Journal Cell Rep PMCID PMC8756379 PMID 34965432 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML