Computational Modeling And Analysis Of Insulin-Induced Eukaryotic Translation Initiation

Abstract

Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this critical question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equations (ODEs) framework. Model parameters were estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints was simultaneously minimized using the multiobjective POETs algorithm. Sensitivity and robustness analysis were used to identify the key regulatory components of the network under different operational conditions. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS1 negative feedback, modulated the relative importance of PI3K and Rheb, but did not fundamentally change the signal flow.