@article{3785,
  keywords = {Animals, Mice, Signal Transduction, Cell Proliferation, High-Throughput Screening Assays, Phosphorylation, MAP Kinase Signaling System, ras Proteins, Optogenetics, Extracellular Signal-Regulated MAP Kinases, Keratinocytes, ErbB Receptors, Proto-Oncogene Proteins c-akt, Drug Evaluation, Preclinical},
  author = {Alexander Goglia and Maxwell Wilson and Siddhartha Jena and Jillian Silbert and Lena Basta and Danelle Devenport and Jared Toettcher},
  title = {A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control.},
  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> },
  year = {2020},
  journal = {Cell Syst},
  volume = {10},
  pages = {240-253.e6},
  month = {2020 Mar 25},
  issn = {2405-4720},
  doi = {10.1016/j.cels.2020.02.005},
  language = {eng},
}