|Title||A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Goglia, AG, Wilson, MZ, Jena, SG, Silbert, J, Basta, LP, Devenport, D, Toettcher, JE|
|Date Published||2020 Mar 25|
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.
|Alternate Journal||Cell Syst|