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

Marc R. Birtwistle, Mariko Hatakeyama, Noriko Yumoto, Babatunde A. Ogunnaike, Jan B. Hoek, Boris N. Kholodenko

Research output: Contribution to journalArticlepeer-review

190 Scopus citations

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.

Original languageEnglish
JournalMolecular Systems Biology
Volume3
DOIs
StatePublished - 2007
Externally publishedYes

Keywords

  • Breast cancer
  • Kinetic analysis
  • Mathematical modeling
  • Receptor tyrosine kinases

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