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Mol Syst Biol. 2007;3:144. Epub 2007 Nov 13.

Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses.

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1
Department of Chemical Engineering, University of Delaware, Newark, DE, USA.

Abstract

Deregulation of ErbB signaling plays a key role in the progression of multiple human cancers. To help understand ErbB signaling quantitatively, in this work we combine traditional experiments with computational modeling, building a model that describes how stimulation of all four ErbB receptors with epidermal growth factor (EGF) and heregulin (HRG) leads to activation of two critical downstream proteins, extracellular-signal-regulated kinase (ERK) and Akt. Model analysis and experimental validation show that (i) ErbB2 overexpression, which occurs in approximately 25% of all breast cancers, transforms transient EGF-induced signaling into sustained signaling, (ii) HRG-induced ERK activity is much more robust to the ERK cascade inhibitor U0126 than EGF-induced ERK activity, and (iii) phosphoinositol-3 kinase is a major regulator of post-peak but not pre-peak EGF-induced ERK activity. Sensitivity analysis leads to the hypothesis that ERK activation is robust to parameter perturbation at high ligand doses, while Akt activation is not.

PMID:
18004277
PMCID:
PMC2132449
DOI:
10.1038/msb4100188
[Indexed for MEDLINE]
Free PMC Article
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