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

Alexander G. Goglia, Maxwell Z. Wilson, Siddhartha G. Jena, Jillian Silbert, Lena P. Basta, Danelle Devenport, Jared E. Toettcher

Research output: Contribution to journalArticle

4 Scopus citations

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 languageEnglish (US)
Pages (from-to)240-253.e6
JournalCell Systems
Volume10
Issue number3
DOIs
StatePublished - Mar 25 2020

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Keywords

  • cell proliferation
  • cell signaling
  • cellular decision-making
  • Erk
  • optogenetics
  • Ras
  • receptor tyrosine kinase
  • signal processing
  • single-cell dynamics

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