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

Sturm, O. E., Orton, R. , Grindlay, J., Birtwistle, M., Vyshemirsky, V. , Gilbert, D., Calder, M. , Pitt, A.R., Kholodenko, B. and Kolch, W. (2010) The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Science Signaling, 3(153), ra90. (doi: 10.1126/scisignal.2001212)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Orton, Dr Richard and Pitt, Dr Andrew and Sturm, Dr Oliver and Calder, Professor Muffy and Gilbert, Prof David and Vyshemirsky, Dr Vladislav
• Authors: Sturm, O. E., Orton, R., Grindlay, J., Birtwistle, M., Vyshemirsky, V., Gilbert, D., Calder, M., Pitt, A.R., Kholodenko, B., and Kolch, W.
• College/School: College of Science and Engineering > School of Computing Science; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Science Signaling
• ISSN: 1937-9145