Journal
CELL SYSTEMS
Volume 10, Issue 3, Pages 240-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2020.02.005
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Funding
- NIH Ruth L. Kirschstein NRSA fellowship [F30CA206408]
- NIH [DP2EB024247]
- NSF CAREER award [1750663]
- NIH training grant [T32GM007388]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1750663] Funding Source: National Science Foundation
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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.
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