Modeling Signal Transduction in Enzyme Cascades with the Concept of Elementary Flux Modes

Abstract

Concepts such as elementary flux modes (EFMs) and extreme pathways are useful tools in the detection of non-decomposable routes (metabolic pathways) in biochemical networks. These methods are based on the fact that metabolic networks obey a mass balance condition. In signal transduction networks, that condition is of minor importance because it is the flow of information that matters. Nevertheless, it would be interesting to apply pathway detection methods to signaling systems. Here, we present a formalism by which this can be achieved in the case of enzyme cascades operating, for example, by phosphorylation and dephosphorylation. It is based on the ideas that the signal is not diminished along each route and that the system has to return to its original state after each signaling event. We illustrate the method by several simple prototypic single-phosphorylation and double-phosphorylation cascades, including convergent and divergent branching. Moreover, it is applied to a specific example from insulin signaling. (See online Supplementary Material at www.liebertonline.com.).

Modelling and mathematical analysis of the M$_{2}$ receptor-dependent joint signalling and secondary messenger network in CHO cells

“…Following Behre & Schuster (2009), we here adapted methods from stoichiometric matrix analysis (EFM analysis, conservation laws, flux sampling) that are usually known in the field of metabolic network analysis and do not require information about kinetic rate constants. These methods operate mainly on the level of a biochemical reaction network.…”

“…The usefulness of applying stoichiometric matrix analysis techniques to signalling pathways has e.g. been demonstrated by Behre & Schuster (2009), who adapted elementary flux mode (EFM) analysis to this situation. We here show, how the known flux sampling technique (Smith, 1996) can be extended to incorporate partially available experimental information (here: cAMP production, phosphodiesterase 4 (PDE4) activation).…”

Modelling of multi-component immunoassay kinetics — A new node-based method for simulation of complex assays

“…Also, the modelling of enzymatic reaction cascades is of interest in drug development mainly to get a better overall view of the biological processes. [29,30,31] In this paper a new method to model multi-component assays with quantitative results is presented. The method uses a network of binding complexes and nodes to calculate and simulate a chemical system.…”

Manatee invariants reveal functional pathways in signaling networks

“…Metabolic systems occur in homeostasis, while signaling pathways display a rather transient and time-dependent behavior. Klamt et al [4], Behre and Schuster [12] and Schuster and Junker [13] have successfully applied the steady-state assumption to signaling networks as well.…”

“…Nevertheless, an algorithm for the computation of feasible TI is lacking. Behre and Schuster [12] have adapted the concept of elementary flux modes to signaling routes in enzyme cascades, in particular for systems consisting of phosphorylation and dephosphorylation cascades. Klamt et al [4] have introduced interaction graphs and logical interaction hypergraphs to analyze the structure of signaling and regulatory networks.…”