Title | A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Goglia, AG, Wilson, MZ, Jena, SG, Silbert, J, Basta, LP, Devenport, D, Toettcher, JE |
Journal | Cell Syst |
Volume | 10 |
Issue | 3 |
Pagination | 240-253.e6 |
Date Published | 2020 03 25 |
ISSN | 2405-4720 |
Keywords | Animals, Cell Proliferation, Drug Evaluation, Preclinical, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, High-Throughput Screening Assays, Keratinocytes, MAP Kinase Signaling System, Mice, Optogenetics, Phosphorylation, Proto-Oncogene Proteins c-akt, ras Proteins, Signal Transduction |
Abstract | <p>Complex, time-varying responses have been observed widely in cell signaling, but how specific dynamics are generated or regulated is largely unknown. One major obstacle has been that high-throughput screens are typically incompatible with the live-cell assays used to monitor dynamics. Here, we address this challenge by screening a library of 429 kinase inhibitors and monitoring extracellular-regulated kinase (Erk) activity over 5 h in more than 80,000 single primary mouse keratinocytes. Our screen reveals both known and uncharacterized modulators of Erk dynamics, including inhibitors of non-epidermal growth factor receptor (EGFR) receptor tyrosine kinases (RTKs) that increase Erk pulse frequency and overall activity. Using drug treatment and direct optogenetic control, we demonstrate that drug-induced changes to Erk dynamics alter the conditions under which cells proliferate. Our work opens the door to high-throughput screens using live-cell biosensors and reveals that cell proliferation integrates information from Erk dynamics as well as additional permissive cues.</p> |
DOI | 10.1016/j.cels.2020.02.005 |
Alternate Journal | Cell Syst |
PubMed ID | 32191874 |
PubMed Central ID | PMC7540725 |
Grant List | DP2 EB024247 / EB / NIBIB NIH HHS / United States F30 CA206408 / CA / NCI NIH HHS / United States T32 GM007388 / GM / NIGMS NIH HHS / United States |