Substratum stiffness regulates Erk signaling dynamics through receptor-level control.

TitleSubstratum stiffness regulates Erk signaling dynamics through receptor-level control.
Publication TypeJournal Article
Year of Publication2021
AuthorsFarahani, PE, Lemke, SB, Dine, E, Uribe, G, Toettcher, JE, Nelson, CM
JournalCell Rep
Volume37
Issue13
Pagination110181
Date Published2021 12 28
ISSN2211-1247
KeywordsCell Movement, Cells, Cultured, Cellular Microenvironment, ErbB Receptors, Extracellular Matrix, Extracellular Signal-Regulated MAP Kinases, Female, Humans, Mammary Glands, Human, Phosphorylation, Signal Transduction
Abstract

<p>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.</p>

DOI10.1016/j.celrep.2021.110181
Alternate JournalCell Rep
PubMed ID34965432
PubMed Central IDPMC8756379
Grant ListU01 CA214292 / CA / NCI NIH HHS / United States
R21 HL110335 / HL / NHLBI NIH HHS / United States
DP2 EB024247 / EB / NIBIB NIH HHS / United States
R01 CA187692 / CA / NCI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States