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A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control

Author(s): Goglia, Alexander G; Wilson, Maxwell Z; Jena, Siddhartha G; Silbert, Jillian; Basta, Lena P; et al

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Abstract: 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.
Publication Date: 25-Mar-2020
Electronic Publication Date: 18-Mar-2020
Citation: Goglia, Alexander G, Wilson, Maxwell Z, Jena, Siddhartha G, Silbert, Jillian, Basta, Lena P, Devenport, Danelle, Toettcher, Jared E. (2020). A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control. Cell systems, 10 (3), 240 - 253.e6. doi:10.1016/j.cels.2020.02.005
DOI: doi:10.1016/j.cels.2020.02.005
ISSN: 2405-4712
EISSN: 2405-4720
Pages: 240 - 253.e6
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Cell Systems
Version: Author's manuscript

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