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

Publication Year
2020

Type

Journal Article
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.

Journal
Cell Syst
Volume
10
Issue
3
Pages
240-253.e6
Date Published
2020 Mar 25
ISSN Number
2405-4720
Alternate Journal
Cell Syst
PMCID
PMC7540725
PMID
32191874