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Control of MAPK signalling: from complexity to what really matters
Jorrit J Hornberg1, Bernd Binder, Frank J Bruggeman
1Department of Molecular Cell Physiology, Institute of Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
Oncogene
|July 12, 2005
Summary
This study reveals that specific reactions, particularly Raf activity, significantly control the epidermal growth factor signaling pathway
Area of Science:
- Systems Biology
- Molecular Biology
- Cancer Research
Background:
- Oncogenesis arises from altered protein kinetics or abundance in cell signaling networks.
- Signaling control is often distributed across multiple components, not confined to a single gene.
- Identifying key reactions is crucial for understanding oncogene function.
Purpose of the Study:
- To develop and apply a novel method for analyzing control in complex signaling networks.
- To identify critical reactions governing the epidermal growth factor (EGF)-induced mitogen-activated protein kinase (MAPK) pathway.
- To understand why certain genes, like Raf, function as oncogenes.
Main Methods:
- Implementation of control analysis on a detailed kinetic model of the EGF-induced MAPK network.
- Quantification of reaction control over ERK phosphorylation amplitude, duration, and integrated output.
- Assessment of distributed control within the signaling network.
Main Results:
- Control is distributed but non-random, with a few reactions dominating signaling.
- Raf activity critically controls all characteristics of extracellular signal-regulated kinase (ERK) phosphorylation.
- Reactions important for one signaling output characteristic are often important for others.
Conclusions:
- The distributed control of signaling networks can be quantitatively assessed.
- Raf's central role in controlling ERK phosphorylation dynamics explains its oncogenic potential.
- The method predicts the impact of mutations and gene expression changes on signaling pathways.