CUED Publications database

Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species

Xu, TR and Vyshemirsky, V and Gormand, A and Von Kriegsheim, A and Girolami, M and Baillie, GS and Ketley, D and Dunlop, AJ and Milligan, G and Houslay, MD and Kolch, W (2010) Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species. Science Signaling, 3. ISSN 1945-0877

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Abstract

The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space, permitting the rational ranking of pathway models. Our approach can use measurements of a limited number of biochemical species when combined with multiple perturbations. As proof of concept, we examined the activation of the extracellular signal-regulated kinase (ERK) pathway by epidermal growth factor. The predicted and experimentally validated model shows that both Raf-1 and, unexpectedly, B-Raf are needed to fully activate ERK in two different cell lines. Thus, our formal methodology rationally infers evidentially supported pathway topologies even when a limited number of biochemical and kinetic measurements are available. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved.

Item Type: Article
Subjects: UNSPECIFIED
Divisions: UNSPECIFIED
Depositing User: Cron Job
Date Deposited: 23 Mar 2020 20:02
Last Modified: 20 Apr 2021 02:01
DOI: 10.1126/scisignal.2000517