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The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier
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File | Description | Size | Format | |
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Paper68.pdf | 398.54 KB |
Author(s)
Date Issued
21 December 2010
Date Available
29T13:12:45Z November 2013
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.
Other Sponsorship
SFI
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
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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