title: Quantitative Analysis of Robustness of Dynamic Response and Signal Transfer in Insulin mediated PI3K/AKT Pathway.
abstract: Robustness is a critical feature of signaling pathways ensuring signal propagation with high fidelity in the event of perturbations. Here we present a detailed quantitative analysis of robustness in insulin mediated PI3K/AKT pathway, a critical signaling pathway maintaining self-renewal in human embryonic stem cells. Using global sensitivity analysis, we identified robustness promoting mechanisms that ensure (1) maintenance of a first order or overshoot dynamics of self-renewal molecule, p-AKT and (2) robust transfer of signals from oscillatory insulin stimulus to p-AKT in the presence of noise. Our results indicate that negative feedback controls the robustness to most perturbations. Faithful transfer of signal from the stimulating ligand to p-AKT occurs even in the presence of noise, albeit with signal attenuation and high frequency cut-off. Negative feedback contributes to signal attenuation, while positive regulators upstream of PIP3contribute to signal amplification. These results establish precise mechanisms to modulate self-renewal molecules like p-AKT.
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Pittsburgh, PA 15261, USA.
authors.forename: Shibin
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Pittsburgh, PA 15261, USA ; Department of Bioengineering, University of Pittsburgh, PA 15219, USA ; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Banerjee
keywords: Global sensitivity analysis; PI3K/AKT pathway; Robust dynamics; Self-renewal; Signal transfer efficiency