Inferring Signaling Pathway Topologies from Multiple Perturbation Measurements of Specific Biochemical Species

Tian-Rui Xu, Vladislav Vyshemirsky, Amélie Gormand, Alex von Kriegsheim, Mark Girolami*, George S. Baillie, Dominic Ketley, Allan J. Dunlop, Graeme Milligan, Miles D. Houslay, Walter Kolch*

*To whom correspondence should be addressed. E-mail: girolami{at}dcs.gla.ac.uk (M.G.) and walter.kolch{at}ucd.ie (W.K.).

This PDF file includes:

• Section 1. The information content in observations of varying chemical species
• Section 2. Methods for biochemical experiments
• Section 3. Mathematical models
• Section 4. Bayesian statistical inference
• Section 5. Sufficiency of data sets used in this study
• References
• Fig. S1. The structure of crosstalk between the cAMP and ERK pathways.
• Fig. S2. Effect of changes in cAMP signaling on EGF-stimulated ERK activation.
• Fig. S3. Rap1 does not interfere with Raf-1 activation and does not mediate cAMP-induced Raf-1 inhibition.
• Fig. S4. Raf-1 and B-Raf localization.
• Figs. S5 to S8. Detailed diagrammatic representation of models 1 through 4.
• Fig. S9. Parameter posterior and the prior for the limiting rate of PKA deactivation in model 2.
• Fig. S10. Parameter posterior for the rate of SOS inhibition with ERK-PP in model 2.
• Fig. S11. Eigenvalues of the correlation matrix for the parameter posterior of model 2.
• Fig. S12. Behaviors predicted for the EGF stimulation of PC12 cells.
• Fig. S13 to S16. Predictions with models 1 through 4.
• Fig. S17. Logarithms of marginal likelihoods for the models used in this study correspond to the weight of experimental evidence supporting each of the corresponding hypotheses.
• Fig. S18. Posterior distributions for SOS activation limiting rate in model 2 inferred from a limited data set.
• Fig. S19. Posterior distribution for K_m in PKA activation by PKA agonist in model 2 inferred from a limited data set.
• Fig. S20. Posterior distribution for K_m in PKA activation by PKA agonist in model 2 inferred from the complete set of data.
• Figs. S21 to S23. Kullback-Leibler divergence values for the parameters of models 1 to 4.
• Table S1. Comparative informativeness of data sets with single-species observations.
• Tables S2 to S9. Tables of experimental data for each experimental condition.

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