Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation

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 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 equation (ODE) framework. A family of model parameters was 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 were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. 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 IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow.胰岛素是调控血液葡萄糖水平的核心激素，可在正常与病变细胞中调控多种细胞及酶促过程。胰岛素信号通过复杂的生化相互作用网络进行传递，最终诱导基因表达程序或翻译起始（translation initiation）等其他生物学过程。令人意外的是，尽管已有大量关于胰岛素信号通路的研究文献，但连接胰岛素与翻译起始的各组分的相对重要性仍不明确。为解答这一问题，我们构建并验证了一系列胰岛素诱导翻译起始的数学模型。该胰岛素网络基于普通微分方程（ordinary differential equation, ODE）框架，采用质量作用动力学进行建模。我们以文献中的24组实验数据集为基础，从初始最优拟合参数集出发，对一系列模型参数进行了估计。采用多目标优化方法，同时最小化模型模拟结果与各实验约束条件之间的残差。通过敏感性分析与鲁棒性分析对模型种群进行验证，我们发现了一个调控翻译起始的胰岛素依赖性开关。分析结果表明，在无胰岛素的状态下，GTP结合蛋白Rheb的促起始活性与PTEN的抗起始活性之间的平衡维持了基础翻译起始水平。另一方面，在存在胰岛素的情况下，PI3K与Rheb的协同活性调控了诱导型翻译起始，且PI3K仅在胰岛素存在时发挥关键作用。其他已知的调控胰岛素作用的机制，例如IRS-1负反馈，仅会改变PI3K与Rheb的相对重要性，并不会从根本上改变信号传导流程。