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

Sturm, Oliver E. and Orton, Richard and Grindlay, Joan and Birtwistle, Marc and Vyshemirsky, Vladislav and Gilbert, David and Calder, Muffy and Pitt, Andrew and Kholodenko, Boris and Kolch, Walter (2010) The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Science signaling, 3 (153). -. ISSN 1937-9145

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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: Article
ID code: 35806
Keywords: protein-kinase cascade, cell fate, MEK, phosphorylation, inhibitors, RAF-1, specificity, activation, network, cancer, Electronic computers. Computer science, Medicine(all)
Subjects: Science > Mathematics > Electronic computers. Computer science
Department: Faculty of Science > Mathematics and Statistics
Related URLs:
Depositing user: Pure Administrator
Date Deposited: 10 Nov 2011 19:29
Last modified: 27 Mar 2014 09:50
URI: http://strathprints.strath.ac.uk/id/eprint/35806

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