4/19/2023 0 Comments Omnigraffle arrowA well-understood model of the KaiABC oscillator, translated into Kappa from the literature, is deployed to demonstrate the DIN and its use in understanding systems dynamics. Specifically, we show how the CM and snapshots provide information about systems capable of polymerization, such as Wnt signaling. We provide use cases illustrating how these concepts generate insight. We discuss details about the computation and rendering of static, dynamic, and causal views of a model, which include the contact map (CM), snaphots at different resolutions, the dynamic influence network (DIN) and causal compression. Our platform is a step in this direction. We argue that, in this approach, modeling is akin to programming and can likewise benefit from an integrated development environment. In addition to these components, we describe the Kappa User Interface, which includes a range of interactive visualization tools for rule-based models needed to make sense of the complexity of biological systems. The main components of the platform are the Kappa Simulator, the Kappa Static Analyzer and the Kappa Story Extractor. We present an overview of the Kappa platform, an integrated suite of analysis and visualization techniques for building and interactively exploring rule-based models. These results reveal how ligand-regulated receptor dimerization dynamics and adaptor protein concentrations play critical roles in EGFR signaling. The predictions were confirmed in studies of cell lines with different expression levels of signaling partners, and in experiments comparing low- and high-affinity ligands and oncogenic EGFR mutants. The model predicted that variations in phosphorylation are dependent on the abundances of signaling partners, while phosphorylation levels are dependent on dimer lifetimes. To understand this heterogeneity, we developed a mathematical model. We found distinct populations of receptors as soon as one min after ligand stimulation, indicating early diversification of function. We found that EGFR is predominantly phosphorylated at multiple sites, yet phosphorylation at specific tyrosines is variable and only a subset of receptors share phosphorylation at the same site, even with saturating ligand concentrations. We extended a single molecule pull-down (SiMPull) technique previously used to study protein-protein interactions to allow for robust measurement of receptor phosphorylation. However, the molecular mechanisms responsible for biased signaling are unresolved due to a lack of insight into the phosphorylation patterns of full-length EGFR. Updates of the stencil package will be made available at the BioNetGen web site ().ĭifferential EGFR phosphorylation is thought to couple receptor activation to distinct signaling pathways. The ESIz also contains instructions for use of the stencil package (see README.txt). OmniGraffle is a general-purpose drawing tool that is commercially available for the Mac platform (The Omni Group, Seattle, WA). In the ESIz, the glyphs shown here are available electronically in the form of an OmniGraffle stencil package (Contact Maps.gstencil). Note that the joining and leaving arrows together equal a cofactor arrow. The 'joining,' 'leaving,' and 'cofactor' arrows are intended for use in combination with chemical reaction arrows. For posttranslational modifications commonly involved in cell signaling, 73 we recommend the following labels: Ac for acetylation, Me for methylation, OH for hydroxylation, p or P for phosphorylation, and Ub for ubiquitination. Thus, 'mR' and 'm:R' are both acceptable forms of a modification flag label. A separator, such as ':', can be inserted between the two parts of a modification flag label. The label 'm' represents a post-translational modification. All of these glyphs are used in example diagrams that follow see the main text for discussion. Boxes, flags, arrows and other symbols that can be used to draw an extended contact map.
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