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Noise Propagation in Two-Step Series MAPK Cascade

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Title Noise Propagation in Two-Step Series MAPK Cascade
 
Creator DHANANJANEYULU, V
SAGAR, PVN
KUMAR, G
VISWANATHAN, GA
 
Subject ACTIVATED PROTEIN-KINASE
TRANSIENT STOCHASTIC DYNAMICS
STEADY-STATE ASSUMPTION
GENE-EXPRESSION
SIGNAL-TRANSDUCTION
MECHANISMS
PATHWAYS
SYSTEMS
TIME
HETEROGENEITY
 
Description Series MAPK enzymatic cascades, ubiquitously found in signaling networks, act as signal amplifiers and play a key role in processing information during signal transduction in cells. In activated cascades, cell-to-cell variability or noise is bound to occur and thereby strongly affects the cellular response. Commonly used linearization method (LM) applied to Langevin type stochastic model of the MAPK cascade fails to accurately predict intrinsic noise propagation in the cascade. We prove this by using extensive stochastic simulations for various ranges of biochemical parameters. This failure is due to the fact that the LM ignores the nonlinear effects on the noise. However, LM provides a good estimate of the extrinsic noise propagation. We show that the correct estimate of intrinsic noise propagation in signaling networks that contain at least one enzymatic step can be obtained only through stochastic simulations. Noise propagation in the cascade depends on the underlying biochemical parameters which are often unavailable. Based on a combination of global sensitivity analysis (GSA) and stochastic simulations, we developed a systematic methodology to characterize noise propagation in the cascade. GSA predicts that noise propagation in MAPK cascade is sensitive to the total number of upstream enzyme molecules and the total number of molecules of the two substrates involved in the cascade. We argue that the general systematic approach proposed and demonstrated on MAPK cascade must accompany noise propagation studies in biological networks.
 
Publisher PUBLIC LIBRARY SCIENCE
 
Date 2014-10-16T14:28:39Z
2014-10-16T14:28:39Z
2012
 
Type Article
 
Identifier PLOS ONE, 7(5)
http://dx.doi.org/10.1371/journal.pone.0035958
http://dspace.library.iitb.ac.in/jspui/handle/100/15785
 
Language en