Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals

Mol Cell. 2013 Jan 24;49(2):249-61. doi: 10.1016/j.molcel.2012.11.002. Epub 2012 Dec 6.

Abstract

The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers. Here, we characterize two central quantitative aspects of this pathway: the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation. Under steady-state conditions, we find that ERK is activated in discrete, asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range. In genetically identical sister cells, cell-to-cell variability in pulse dynamics influences the decision to enter S phase. While targeted inhibition of EGFR reduces the frequency of ERK activity pulses, inhibition of MEK reduces their amplitude. Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ~10%, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzamides / pharmacology
  • Cell Line
  • Cell Proliferation*
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Enzyme Activation
  • Epidermal Growth Factor / physiology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gefitinib
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System*
  • Microscopy, Fluorescence
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Quinazolines / pharmacology
  • S Phase Cell Cycle Checkpoints
  • Time-Lapse Imaging

Substances

  • Benzamides
  • PD 0325901
  • Quinazolines
  • Epidermal Growth Factor
  • Diphenylamine
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Gefitinib