1. Substratum stiffness regulates Erk signaling dynamics through receptor-level control
- Author
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Payam E. Farahani, Sandra B. Lemke, Elliot Dine, Giselle Uribe, Jared E. Toettcher, and Celeste M. Nelson
- Subjects
0303 health sciences ,General Biochemistry, Genetics and Molecular Biology ,Article ,Extracellular Matrix ,ErbB Receptors ,03 medical and health sciences ,0302 clinical medicine ,Cellular Microenvironment ,Cell Movement ,Humans ,Female ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Mammary Glands, Human ,030217 neurology & neurosurgery ,Cells, Cultured ,030304 developmental biology ,Signal Transduction - Abstract
SUMMARY 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., Graphical Abstract, In brief Farahani et al. investigate how soft microenvironments limit signal transmission through the EGFR/Erk pathway. Optogenetic stimulation reveals that the intracellular portion of the EGFR/Erk pathway remains signaling competent regardless of substratum stiffness. Rather, soft microenvironments limit Erk signaling by decreasing interactions between EGFR and its cognate ligand.
- Published
- 2021