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Index analysis: An approach to understand signal transduction with application to the EGFR signalling pathway

Authors: Jane Knöchel; Charlotte Kloft; Wilhelm Huisinga;

Index analysis: An approach to understand signal transduction with application to the EGFR signalling pathway

Abstract

In systems biology and pharmacology, large-scale kinetic models are used to study the dynamic response of a system to a specific input or stimulus. While in many applications, a deeper understanding of the input-response behaviour is highly desirable, it is often hindered by the large number of molecular species and the complexity of the interactions. An approach that identifies key molecular species for a given input-response relationship and characterises dynamic properties of states is therefore highly desirable. We introduce the concept of index analysis; it is based on different time- and state-dependent quantities (indices) to identify important dynamic characteristics of molecular species. All indices are defined for a specific pair of input and response variables as well as for a specific magnitude of the input. In application to a large-scale kinetic model of the EGFR signalling cascade, we identified different phases of signal transduction, the peculiar role of Phosphatase3 during signal activation and Ras recycling during signal onset. In addition, we discuss the challenges and pitfalls of interpreting the relevance of molecular species based on knock-out simulation studies, and provide an alternative view on conflicting results on the importance of parallel EGFR downstream pathways. Beyond the applications in model interpretation, index analysis is envisioned to be a valuable tool in model reduction.

Keywords

sensitivity-based input-response indices, QH301-705.5, Systems Biology, Signaling cascades, 500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie, EGFR system, Quantitative Biology - Quantitative Methods, Models, Biological, ErbB Receptors, model interpretation, index analysis, Signaling networks, FOS: Biological sciences, Computer Simulation, Biology (General), EGFR signaling, Quantitative Methods (q-bio.QM), Research Article, Signal Transduction

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selected citations
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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