Ligand-dependent Responses of the ErbB Signaling Network: Experimental and Modeling Analyses

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2007 Nov 16

PMID 18004277

Citations 122

Authors

Marc R Birtwistle

Mariko Hatakeyama

Noriko Yumoto

Babatunde A Ogunnaike

Jan B Hoek

Boris N Kholodenko

Affiliations

Soon will be listed here.

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.

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