Control of MAPK signalling: from complexity to what really matters.

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Hornberg JJ,Binder B,Bruggeman FJ,Schoeberl B,Heinrich R,Westerhoff HV

doi

10.1038/sj.onc.1208817

subject

Has Abstract

pub_date

2005-08-25 00:00:00

pages

5533-42

issue

36

eissn

0950-9232

issn

1476-5594

pii

1208817

journal_volume

24

pub_type

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