@article{dcf7f6dbf18b4dc4a5bebe90cbd9e11a,
title = "Substratum stiffness regulates Erk signaling dynamics through receptor-level control",
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 = "MAP kinase, morphodynamics, receptor tyrosine kinase, signaling dynamics, tissue mechanics",
author = "Farahani, {Payam E.} and Lemke, {Sandra B.} and Elliot Dine and Giselle Uribe and Toettcher, {Jared E.} and Nelson, {Celeste M.}",
note = "Funding Information: We thank all members of the Nelson and Toettcher labs for their insights and comments, Katherine Rittenbach and Christina DeCoste of the Princeton Molecular Biology Flow Cytometry Resource Center for assistance with cell sorting, and Gary Laevsky from the Princeton Nikon Imaging Facility for assistance with microscopy. This work was supported in part by grants from the National Science Foundation (NSF CAREER Award 1750663 to J.E.T.), the National Institutes of Health (grants HL110335 , HL118532 , HL120142 , CA187692 , and CA214292 to C.M.N. and grant DP2EB024247 to J.E.T.), and a Faculty Scholars Award from the Howard Hughes Medical Institute (to C.M.N.). P.E.F. was supported in part by the NSF Graduate Research Fellowship Program. Funding Information: We thank all members of the Nelson and Toettcher labs for their insights and comments, Katherine Rittenbach and Christina DeCoste of the Princeton Molecular Biology Flow Cytometry Resource Center for assistance with cell sorting, and Gary Laevsky from the Princeton Nikon Imaging Facility for assistance with microscopy. This work was supported in part by grants from the National Science Foundation (NSF CAREER Award 1750663 to J.E.T.), the National Institutes of Health (grants HL110335, HL118532, HL120142, CA187692, and CA214292 to C.M.N. and grant DP2EB024247 to J.E.T.), and a Faculty Scholars Award from the Howard Hughes Medical Institute (to C.M.N.). P.E.F. was supported in part by the NSF Graduate Research Fellowship Program. Conceptualization, P.E.F. C.M.N. and J.E.T.; Methodology, P.E.F. C.M.N. and J.E.T.; Investigation, P.E.F. S.B.L. E.D. and G.U.; Resources, P.E.F. E.D. G.U. C.M.N. and J.E.T.; Writing and Editing, P.E.F. C.M.N. and J.E.T.; Funding Acquisition and Supervision, C.M.N. and J.E.T. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = dec,
day = "28",
doi = "10.1016/j.celrep.2021.110181",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}