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Sci. Signal., 21 December 2010
Vol. 3, Issue 153, p. ra90
[DOI: 10.1126/scisignal.2001212]

RESEARCH ARTICLES

The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier

Oliver E. Sturm1*{dagger}, Richard Orton1*{ddagger}, Joan Grindlay2*, Marc Birtwistle3, Vladislav Vyshemirsky1§, David Gilbert1||, Muffy Calder1, Andrew Pitt4, Boris Kholodenko3, and Walter Kolch3,5

1 Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK.
2 Signalling and Proteomics Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
3 Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
4 Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
5 Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

* These authors contributed equally to this work.

{dagger} Present address: Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38104, USA.

{ddagger} Present address: Comparative Epidemiology Group, Faculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, UK.

§ Present address: Department of Mathematics and Statistics, University of Strathclyde, Glasgow G1 1XH, UK.

|| Present address: School of Information Systems, Computing and Mathematics, Brunel University, Uxbridge, Middlesex UB8 3PH, UK.

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.

¶ To whom correspondence should be addressed. E-mail: walter.kolch{at}ucd.ie

Citation: O. E. Sturm, R. Orton, J. Grindlay, M. Birtwistle, V. Vyshemirsky, D. Gilbert, M. Calder, A. Pitt, B. Kholodenko, W. Kolch, The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier. Sci. Signal. 3, ra90 (2010).

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