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Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model.

ABSTRACT: BACKGROUND:Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-?1 (TGF-?1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-?1 depends on the balance between two antagonistic sub-pathways. RESULTS:Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-?1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS?-?TGF-?1?-?PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS?-?TGF-?1?-?PAI1 loop. CONCLUSIONS:Using the TGF-?1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS?-?TGF-?1?-?PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications.

SUBMITTER: Li H

PROVIDER: S-EPMC5763301 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-β1 activation model.

Li Huipeng H Venkatraman Lakshmi L Narmada Balakrishnan Chakrapani BC White Jacob K JK Yu Hanry H Tucker-Kellogg Lisa L

BMC systems biology 20171221 Suppl 7

<h4>Background</h4>Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-β1 (TGF-β1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-β1 depends on the balance between two antagonistic sub-pathways.<h4>Results</h4>Through modeling ...[more]

PMID: 29322934

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Project description:BackgroundTransforming growth factor β (TGF-β) signalling regulates the development of embryos and tissue homeostasis in adults. In conjunction with other oncogenic changes, long-term perturbation of TGF-β signalling is associated with cancer metastasis. Although TGF-β signalling can be complex, many of the signalling components are well defined, so it is possible to develop mathematical models of TGF-β signalling using reduction and scaling methods. The parameterization of our TGF-β signalling model is consistent with experimental data.ResultsWe developed our mathematical model for the TGF-β signalling pathway, i.e. the RF- model of TGF-β signalling, using the "rapid equilibrium assumption" to reduce the network of TGF-β signalling reactions based on the time scales of the individual reactions. By adding time-delayed positive feedback to the inherent time-delayed negative feedback for TGF-β signalling. We were able to simulate the sigmoidal, switch-like behaviour observed for the concentration dependence of long-term (> 3 hours) TGF-β stimulation. Computer simulations revealed the vital role of the coupling of the positive and negative feedback loops on the regulation of the TGF-β signalling system. The incorporation of time-delays for the negative feedback loop improved the accuracy, stability and robustness of the model. This model reproduces both the short-term and long-term switching responses for the intracellular signalling pathways at different TGF-β concentrations. We have tested the model against experimental data from MEF (mouse embryonic fibroblasts) WT, SV40-immortalized MEFs and Gp130 F/F MEFs. The predictions from the RF- model are consistent with the experimental data.ConclusionsSignalling feedback loops are required to model TGF-β signal transduction and its effects on normal and cancer cells. We focus on the effects of time-delayed feedback loops and their coupling to ligand stimulation in this system. The model was simplified and reduced to its key components using standard methods and the rapid equilibrium assumption. We detected differences in short-term and long-term signal switching. The results from the RF- model compare well with experimental data and predict the dynamics of TGF-β signalling in cancer cells with different mutations.

Dataset Information

Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model.

Publications

Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-β1 activation model.

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