Stochastic ERK activation induced by noise and cell-to-cell propagation regulate cell density-dependent proliferation.. Rattus norvegicus

The ERK MAP kinase plays a central role in the signaling cascades of cell growth. Here, we show that stochastic ERK activity pulses regulate cell proliferation rates in a cell density-dependent manner. A FRET biosensor revealed stochastic ERK activity pulses fired spontaneously or propagated from adjacent cells. Frequency, but not amplitude, of ERK activity pulses exhibited a bell-shaped response to the cell density and correlated with cell proliferation rates. Consistently, synthetic ERK activity pulses generated by a light-switchable CRaf protein accelerated cell proliferation. A mathematical model clarified that 80% and 20% of ERK activity pulses are generated by the noise and cell-to-cell propagation, respectively. Finally,RNA-Seq analysis of cells subjected to the synthetic ERK activity pulses suggested the involvement of SRF transcription factors in the gene expression driven by the ERK activity pulses. Taken together, these findings reveal a role of the stochastic ERK activity pulses in cell proliferation.