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.
Highlights
Multistability in signalingMolecular switches play an important role in cell signaling
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
Summary
Multistability in signalingMolecular switches play an important role in cell signaling. It is known that transcriptional switches control differentiation decisions [1] and major developmental signaling pathways use different mechanisms to switch from transcriptional repression to activation of target genes [2]. Instead of a mere ultrasensitive response (sigmoid input-output relationship steeper than the Michaelis–Menten type [3]), switch-like systems undergo a transition between two discrete outcomes, often accompanied by hysteresis. In the context of mathematical models of ordinary differential equations (ODEs), switch-like behavior is captured by the nonlinear phenomenon of bistability where two stable steady states coexist for a certain range of the model parameters. A bistable system can switch between two different stable steady states in a threshold dependent manner, producing a sharp change in the output as a response to a gradual change in a stimulus or control parameter. Reaction networks may have more than two different steady states, as it is the case for multi-site phosphorylation systems [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
