Stochastic ERK Activation Induced by Noise and Cell-To-Cell Propagation Regulates Cell Density-Dependent Proliferation

Mol Cell. 2013 Nov 21;52(4):529-40. doi: 10.1016/j.molcel.2013.09.015. Epub 2013 Oct 17.

Abstract

The extracellular signal-regulated kinase (ERK) 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 fluorescence resonance energy transfer (FRET) biosensor revealed that 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 sequencing analysis of cells subjected to the synthetic ERK activity pulses suggested the involvement of serum responsive factor (SRF) transcription factors in the gene expression driven by the ERK activity pulses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Benzamides / pharmacology
  • Cell Communication
  • Cell Count
  • Cell Line
  • Cell Proliferation*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation
  • Humans
  • Imidazoles / pharmacology
  • Kinetics
  • MAP Kinase Signaling System*
  • Models, Biological
  • Promoter Regions, Genetic
  • Rats
  • Sequence Analysis, RNA
  • Stochastic Processes
  • Time-Lapse Imaging
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / metabolism

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Benzamides
  • Imidazoles
  • SB-590885
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • SRA/DRX0012476
  • SRA/DRX0012477
  • SRA/DRX0012478
  • SRA/DRX0012479
  • SRA/DRX0012480
  • SRA/DRX0012481