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.
Original language | English (US) |
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Pages (from-to) | 240-253.e6 |
Journal | Cell Systems |
Volume | 10 |
Issue number | 3 |
DOIs | |
State | Published - Mar 25 2020 |
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Histology
- Cell Biology
Keywords
- Erk
- Ras
- cell proliferation
- cell signaling
- cellular decision-making
- optogenetics
- receptor tyrosine kinase
- signal processing
- single-cell dynamics