Strong Negative Feedback From Erk to Raf Confers Robustness to MAPK Signalling

Mol Syst Biol. 2011 May 24;7:489. doi: 10.1038/msb.2011.27.

Abstract

Protein levels within signal transduction pathways vary strongly from cell to cell. Here, we analysed how signalling pathways can still process information quantitatively despite strong heterogeneity in protein levels. We systematically perturbed the protein levels of Erk, the terminal kinase in the MAPK signalling pathway in a panel of human cell lines. We found that the steady-state phosphorylation of Erk is very robust against perturbations of Erk protein level. Although a multitude of mechanisms exist that may provide robustness against fluctuating protein levels, we found that one single feedback from Erk to Raf-1 accounts for the observed robustness. Surprisingly, robustness is provided through a fast post-translational mechanism although variation of Erk levels occurs on a timescale of days.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Cell Proliferation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Feedback, Physiological*
  • Gene Silencing
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mathematical Computing
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-raf* / genetics
  • Proto-Oncogene Proteins c-raf* / metabolism
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Transfection

Substances

  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases