Hornberg, Binder, Bruggeman, Schoeberl, Heinrich, Westerhoff, 2005

Model Status

This CellML model runs in both OpenCell and COR to recreate the published results. Thank you to the model author Jorrit Hornberg for providing us with the original mathematica code, and also to Joe Cursons for the hours he has spent debugging the CellMl model. Please note there are several differences between the original CellML version of this model (which was based on the published paper), and the current version of the model (which was based on the Mathematica code). These differences are listed here as a PDF document.

Model Structure

ABSTRACT:

ABSTRACT: Oncogenesis results from changes in kinetics or in abundance of proteins in signal transduction networks. Recently, it was shown that control of signalling cannot reside in a single gene product, and might well be dispersed over many components. Which of the reactions in these complex networks are most important, and how can the existing molecular information be used to understand why particular genes are oncogenes whereas others are not? We implement a new method to help address such questions. We apply control analysis to a detailed kinetic model of the epidermal growth factor-induced mitogen-activated protein kinase network. We determine the control of each reaction with respect to three biologically relevant characteristics of the output of this network: the amplitude, duration and integrated output of the transient phosphorylation of extracellular signal-regulated kinase (ERK). We confirm that control is distributed, but far from randomly: a small proportion of reactions substantially control signalling. In particular, the activity of Raf is in control of all characteristics of the transient profile of ERK phosphorylation, which may clarify why Raf is an oncogene. Most reactions that really matter for one signalling characteristic are also important for the other characteristics. Our analysis also predicts the effects of mutations and changes in gene expression.

The original paper reference is cited below:

Control of MAPK signalling: from complexity to what really matters, Jorrit J Hornberg, Bernd Binder, Frank J Bruggeman, Birgit Schoeberl, Reinhart Heinrich and Hans V Westerhoff, 2005, Oncogene, 26, 117-125. PubMed ID: 16007170

Schematic diagram of the signal transduction nectwork described by the model.