Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation

Varner JD (2011) Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation. PLoS Comput Biol 7(11): e1002263. doi:10.1371/journal.pcbi.1002263 Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation Joshua Lequieu 0 Anirikh Chakrabarti 0 Satyaprakash Nayak 0 Jeffrey D. Varner 0 Markus W. Covert, Stanford University, United States of America 0 School of Chemical and Biomolecular Engineering, Cornell University , Ithaca, New York , United States of America 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 GTPbinding 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. - Funding: This study was supported by Award Number #U54CA143876 from the National Cancer Institute (support to A.C) and the National Science Foundation award number #DGE-1011509 for the support of J.L. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. 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 [17]. The regulation of cellular function by insulin and insulin-like growth factors I/II (IGF-I/II) is a highly complex process [814]. Insulin and IGF-I/ II interact with insulin receptors (IR), and type I/II IGF receptors (IGF-IR/IIR) in addition to other transmembrane receptors [10]. These interactions ultimately induce gene expression programs or other processes such as translation initiation. Translation rates of many cell cycle and survival proteins are modulated by growth factor, hormone or other mitogenic signals [15]. Insulin induces the activation of class I Phosphoinositide 3-kinases (PI3Ks), which in turn activate the serine/threonine protein kinase Akt and the mammalian target of rapamycin (mTOR). The PI3K/Akt/ mTOR signaling axis is important to a variety of cellular programs, including apoptosis [16], cell size control [17] and translation initiation. Among other functions, activation of the PI3K/Akt/mTOR axis results in the phosphorylation of eukaryotic translation initiation factor 4E-binding protein (4E-BPx) family members [18]. Phosphorylation of 4E-BPx causes the release of the eukaryotic translation initiation factor 4E (eIF4E), which is critical to directing ribosomes to the 7-methyl-guanosine cap of eukaryotic mRNAs. Previously, the availability of eIF4E has been shown to be rate limiting for translation initiation in many eukaryotic cell-lines [15,19]. Given its central role in cell biology, evolutionarily optimized infrastructure like translation might be expected to be robust or highly redundant. Surprisingly, deregulated translation, especially involving growth-factor or insulin induced initiation mechanisms, has been implicated in a spectrum of cancers [20]. Despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. Many investigators have explored this question using both experimental and computational tools. For example, Caron et al. recently published a comprehensive map of the mTOR signaling network, including a detailed portrait of insulin induced mTOR activation and its downstream role in translation initiation [21]. Taniguchi et al. proposed three criteria to identify the critical nodes of insulin signaling: network divergence, degree of regulation and potential crosstalk [10]. Using these criteria, they identified insulin-receptor (IR), PI3K and Akt as the critical nodes of insulin action. Several insightful mathematical models of insulin-signaling have also been published [2225]. While these models vary in their focus and biological scope, none has exclusively focused on how insulin stimulates translation initiation. This particular question was addressed by Insulin is a hormone produced by the body that regulates uptake of glucose from the bloodstream. The cellular response to insulin is governed by a complex network of intracellular interactions that ultimately influence cell growth and metabolism. Because of its central role in physiology, insulin signaling has been extensively studied. Yet despite this wealth of research, the relative importance of components in insulin signaling remains unclear. Mechanistic computer simulations have been shown to provide insight into the function of complex systems, such as insulin signaling. In this work we constructed and interrogated a mathematical computer simulation of insulin signaling to better understand the important components of the insulin signaling network. We determined the most important network components and identified network perturbations that can induce dramatic shifts in cellular phenotype. Our results offer an in-depth analysis of the insulin signaling pathway and provide a unique paradigm towards understanding how malfunctions in insulin signaling can result in numerous disease states. Nayak et al., who analyzed a family of detailed mathematical model (...truncated)