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

206 Citations (Scopus)


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
Article numberra90
Number of pages7
JournalScience Signaling
Issue number153
Publication statusPublished - 21 Dec 2010


  • protein-kinase cascade
  • cell fate
  • MEK
  • phosphorylation
  • inhibitors
  • RAF-1
  • specificity
  • activation
  • network
  • cancer


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