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      Chemical Reaction Network Theory elucidates sources of multistability in interferon signaling

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          Abstract

          Bistability has important implications in signaling pathways, since it indicates a potential cell decision between alternative outcomes. We present two approaches developed in the framework of the Chemical Reaction Network Theory for easy and efficient search of multiple steady state behavior in signaling networks (both with and without mass conservation), and apply them to search for sources of bistability at different levels of the interferon signaling pathway. Different type I interferon subtypes and/or doses are known to elicit differential bioactivities (ranging from antiviral, antiproliferative to immunomodulatory activities). How different signaling outcomes can be generated through the same receptor and activating the same JAK/STAT pathway is still an open question. Here, we detect bistability at the level of early STAT signaling, showing how two different cell outcomes are achieved under or above a threshold in ligand dose or ligand-receptor affinity. This finding could contribute to explain the differential signaling (antiviral vs apoptotic) depending on interferon dose and subtype ( α vs β) observed in type I interferons.

          Author summary

          Type I interferons (IFNs) regulate a variety of cell functions, exhibiting, amongst others, antiviral, antiproliferative and immunomodulatory activities. Due to their anticancer effects, type I IFNs have a long record of applications in clinical oncology. It is still an open question how type I IFNs generate so diverse signaling outcomes by activating the same receptor at the cell membrane and triggering the same JAK/STAT pathway. It has been experimentally shown that differences in ligand affinity towards the receptor, IFN dose and receptor density are translated into different activities, but the underlying mechanisms of differential responses remain elusive. Looking for potential cell decision processes that could help answering this question, we explore the capacity for bistability at different levels of the IFN pathway. The search for bistability sources in interferon signaling is performed within the framework of Chemical Reaction Network Theory, by adapting previous results to the specific context of signaling pathways. Surprisingly, we find a source of bistability already at the early STAT signaling level. As a result, we show that the pathway has the capacity to translate a difference in affinity or IFN dose into a binary decision between High/Low or Low/High activation profiles of two IFN transcription factors (ISGF3 and STAT1-STAT1 homodimers) responsible for the upregulation of two different families of interferon stimulated genes: ISRE and GAS.

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          Most cited references 54

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          Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors.

          We present a computational model that offers an integrated quantitative, dynamic, and topological representation of intracellular signal networks, based on known components of epidermal growth factor (EGF) receptor signal pathways. The model provides insight into signal-response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade. It shows that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration and that the critical parameter in determining signal efficacy is the initial velocity of receptor activation. The predictions of the model agree well with experimental analysis of the effect of EGF on two downstream responses, phosphorylation of ERK-1/2 and expression of the target gene, c-fos.
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            Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2.

            In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, whose robust biochemical rhythm continues even when DNA replication or mitosis is blocked. At the core of the oscillator is a negative feedback loop; cyclins accumulate and produce active mitotic Cdc2-cyclin B; Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback, with active Cdc2-cyclin B stimulating its activator Cdc25 (refs 5-7) and inactivating its inhibitors Wee1 and Myt1 (refs 8-11). Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. Therefore, we examined whether Cdc2 activation is bistable. We confirm that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switch-like, as would be expected if Cdc2 activation were bistable. We also show that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator.
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              Metabolic network structure determines key aspects of functionality and regulation.

              The relationship between structure, function and regulation in complex cellular networks is a still largely open question. Systems biology aims to explain this relationship by combining experimental and theoretical approaches. Current theories have various strengths and shortcomings in providing an integrated, predictive description of cellular networks. Specifically, dynamic mathematical modelling of large-scale networks meets difficulties because the necessary mechanistic detail and kinetic parameters are rarely available. In contrast, structure-oriented analyses only require network topology, which is well known in many cases. Previous approaches of this type focus on network robustness or metabolic phenotype, but do not give predictions on cellular regulation. Here, we devise a theoretical method for simultaneously predicting key aspects of network functionality, robustness and gene regulation from network structure alone. This is achieved by determining and analysing the non-decomposable pathways able to operate coherently at steady state (elementary flux modes). We use the example of Escherichia coli central metabolism to illustrate the method.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, CA USA )
                1553-734X
                1553-7358
                April 2017
                3 April 2017
                : 13
                : 4
                Affiliations
                Department of Biosystems Science and Engineering and Swiss Institute of Bioinformatics, ETH Zurich, Zurich, Switzerland
                University of Illinois at Urbana-Champaign, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Analyzed the data: IOM PY JS.

                • Wrote the paper: IOM PY JS.

                • Conceived and designed the research: IOM JS.

                • Designed and developed the methods used in analysis: IOM.

                • Performed the research: IOM PY JS.

                [¤]

                Current address: BioProcess Engineering Group, IIM-CSIC (Spanish National Research Council), Vigo, Spain

                Article
                PCOMPBIOL-D-15-01939
                10.1371/journal.pcbi.1005454
                5400276
                28369103
                © 2017 Otero-Muras et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 6, Tables: 0, Pages: 28
                Product
                Funding
                Funded by: EU FP7 project IFNAction (contract 223608)
                We gratefully acknowledge financial support by the European Union FP7 project IFNaction (‘A system view on the differential activities of human type I interferons’; project reference: 223608) to JS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Interferons
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                STAT signaling
                Physical Sciences
                Physics
                Physical Laws and Principles
                Conservation of Mass
                Computer and Information Sciences
                Network Analysis
                Signaling Networks
                Physical Sciences
                Chemistry
                Physical Chemistry
                Chemical Equilibrium
                Physical Sciences
                Mathematics
                Optimization
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Physical Sciences
                Chemistry
                Chemical Reactions
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-04-21
                All relevant data are within the paper and its Supporting Information files.

                Quantitative & Systems biology

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