Agents in Biology
177
receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based
approaches. The method also permits consideration of structural parameters in pathway regulation. The modelers predicted that inhibition of
NFκB is directly affected by actin filaments of the cytoskeleton sequestering excess inhibitors, therefore regulating steady-state and feedback
behavior [149].
Computational modeling of NFκB activation using IL-1RI and its coreceptor TILRR, predicts a role for cytoskeletal sequestration of IκBα in
inflammatory signalling. The transcription factor NFκB is activated by
toll-like receptors and controlled by mechanotransduction and changes
in the cytoskeleton. In this study we combine 3-D predictive protein
modeling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NFκB. Simulations
used a comprehensive agent-based model of the NFκB pathway, which
includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent-based modeling
relies on in silico reproductions of systems through the interactions of
its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex
formation and translocation of regulatory components. The modelers
showed that their model faithfully reproduced the multiple steps comprising the NFκB pathway, and provided a framework from which they
can explore novel aspects of the system. The initial analysis, using 3D
predictive protein modeling and in vitro assays, demonstrated that the
inhibitor IκBα is sequestered to the actin/spectrin complex within the
cytoskeleton of the resting cell, and released during IL-1 stimulation,
through a process controlled by the IL-1RI co-receptor TILRR. In silico
simulations using the agent-based model predict that the cytoskeletal
pool of IκBα is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for
signal calibration and enables efficient, activation-sensitive regulation of
NFκB and inflammatory responses [161].
MapKinase pathways. Signal transduction through the Mitogen Activated
Protein Kinase (MAPK) pathways. Many cells use these pathways to
interpret changes to their environment and respond accordingly. The
pathways are central to triggering diverse cellular responses such as
survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they are capable of maintaining a high level of fidelity and specificity to the original signal. There are numerous theories explaining
how fidelity and specificity arise within this complex context; spatiotemporal regulation of the pathways and feedback loops are thought
to be very important. This experiment presents an agent-based com-
177
receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based
approaches. The method also permits consideration of structural parameters in pathway regulation. The modelers predicted that inhibition of
NFκB is directly affected by actin filaments of the cytoskeleton sequestering excess inhibitors, therefore regulating steady-state and feedback
behavior [149].
Computational modeling of NFκB activation using IL-1RI and its coreceptor TILRR, predicts a role for cytoskeletal sequestration of IκBα in
inflammatory signalling. The transcription factor NFκB is activated by
toll-like receptors and controlled by mechanotransduction and changes
in the cytoskeleton. In this study we combine 3-D predictive protein
modeling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NFκB. Simulations
used a comprehensive agent-based model of the NFκB pathway, which
includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent-based modeling
relies on in silico reproductions of systems through the interactions of
its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex
formation and translocation of regulatory components. The modelers
showed that their model faithfully reproduced the multiple steps comprising the NFκB pathway, and provided a framework from which they
can explore novel aspects of the system. The initial analysis, using 3D
predictive protein modeling and in vitro assays, demonstrated that the
inhibitor IκBα is sequestered to the actin/spectrin complex within the
cytoskeleton of the resting cell, and released during IL-1 stimulation,
through a process controlled by the IL-1RI co-receptor TILRR. In silico
simulations using the agent-based model predict that the cytoskeletal
pool of IκBα is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for
signal calibration and enables efficient, activation-sensitive regulation of
NFκB and inflammatory responses [161].
MapKinase pathways. Signal transduction through the Mitogen Activated
Protein Kinase (MAPK) pathways. Many cells use these pathways to
interpret changes to their environment and respond accordingly. The
pathways are central to triggering diverse cellular responses such as
survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they are capable of maintaining a high level of fidelity and specificity to the original signal. There are numerous theories explaining
how fidelity and specificity arise within this complex context; spatiotemporal regulation of the pathways and feedback loops are thought
to be very important. This experiment presents an agent-based com-