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

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Title: The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier
Authors: Sturm, O. E.
Orton, Richard J.
Grindlay, J.
et al.
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Date: 21-Dec-2010
Online since: 2013-11-29T13:12:45Z
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.
Type of material: Journal Article
Publisher: American Association for the Advancement of Science
Journal: Science Signaling
Volume: 3
Issue: 153
Start page: ra90
End page: ra90
Copyright (published version): 2010 American Association for the Advancement of Science
Keywords: mammalian MAPK/ERK pathwaythree-tiered kinase amplifier modulenegative feedback amplifier
DOI: 10.1126/scisignal.2001212
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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