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Control of MAPK signalling: from complexity to what really matters

Oncogene volume 24, pages 5533–5542 (2005)Cite this article

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.

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Abbreviations

EGF:

epidermal growth factor

EGFR:

EGF receptor

ERK:

extracellular signal-regulated kinase

ERK-PP:

doubly phosphorylated ERK

Grb2:

growth factor receptor binding protein 2

MAPK:

mitogen-activated protein kinase

MCA:

metabolic control analysis

MEK:

MAPK/ERK kinase

Shc:

Src homology and collagen domain protein

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Acknowledgements

We thank Jan Lankelma for stimulating discussions. This work was partly sponsored by a joint grant of the Netherlands Organization for Scientific Research (NWO) and the German Research Foundation (DFG) to stimulate collaborations between Dutch and German graduate schools.

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Author notes

  1. Jorrit J Hornberg, Bernd Binder and Frank J Bruggeman: These authors have contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Cell Physiology, Institute of Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands

    Jorrit J Hornberg, Frank J Bruggeman & Hans V Westerhoff

  2. Department of Theoretical Biophysics, Humboldt University, Berlin, Germany

    Bernd Binder & Reinhart Heinrich

  3. Merrimack Pharmaceuticals, Cambridge, MA, USA

    Birgit Schoeberl

  4. Mathematical Biochemistry, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands

    Hans V Westerhoff

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  1. Jorrit J Hornberg
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Correspondence to Hans V Westerhoff.

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Hornberg, J., Binder, B., Bruggeman, F. et al. Control of MAPK signalling: from complexity to what really matters. Oncogene 24, 5533–5542 (2005). https://doi.org/10.1038/sj.onc.1208817

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