Elucidating the in vivo phosphorylation dynamics of the ERK MAP kinase using quantitative proteomics data and Bayesian model selection

Abstract

Ever since reversible protein phosphorylation was discovered, it has been clear that it plays a key role in the regulation of cellular processes. Proteins often undergo double phosphorylation, which can occur through two possible mechanisms: distributive or processive. Which phosphorylation mechanism is chosen for a particular cellular regulation bears biological significance, and it is therefore in our interest to understand these mechanisms. In this paper we study dynamics of the MEK/ERK phosphorylation. We employ a model selection algorithm based on approximate Bayesian computation to elucidate phosphorylation dynamics from quantitative time course data obtained from PC12 cells in vivo. The algorithm infers the posterior distribution over four proposed models for phosphorylation and dephosphorylation dynamics, and this distribution indicates the amount of support given to each model. We evaluate the robustness of our inferential framework by systematically exploring different ways of parameterizing the models and for different prior specifications. The models with the highest inferred posterior probability are the two models employing distributive dephosphorylation, whereas we are unable to choose decisively between the processive and distributive phosphorylation mechanisms.