The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier

Oliver E. Sturm, Richard Orton, Joan Grindlay, Marc Birtwistle, Vladislav Vyshemirsky, David Gilbert, Muffy Calder, Andrew Pitt, Boris Kholodenko, Walter Kolch

Research output: Contribution to journalArticlepeer-review

Abstract

Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.
Original languageEnglish
Pages (from-to)ra90
JournalScience Signaling
Volume3
Issue number153
DOIs
Publication statusPublished - 21 Dec 2010

Keywords

  • animals
  • butadienes
  • cell membrane
  • extracellular signal-regulated MAP kinases
  • physiological feedback
  • flow cytometry
  • guanine nucleotide exchange factors
  • guanosine triphosphate
  • immunoblotting
  • immunoprecipitation
  • indoles
  • kinetics
  • MAP kinase kinase kinases
  • metabolic networks and pathways
  • mice
  • theoretical models
  • NIH 3T3 cells
  • nitriles
  • phosphorylation
  • quinazolines
  • signal transduction
  • ras proteins

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