Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species.
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.
Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G128QQ, UK.
Tian-Rui
TR
Xu
Vladislav
V
Vyshemirsky
Amélie
A
Gormand
Alex
A
von Kriegsheim
Mark
M
Girolami
George S
GS
Baillie
Dominic
D
Ketley
Allan J
AJ
Dunlop
Graeme
G
Milligan
Miles D
MD
Houslay
Walter
W
Kolch
D000818:Animals; D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047468:Immunoprecipitation; D008954:Models, Biological; D016716:PC12 Cells; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases