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

Mol Syst Biol. 2007:3:144. doi: 10.1038/msb4100188. Epub 2007 Nov 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androstadienes / pharmacology
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Dimerization
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological / drug effects
  • Humans
  • Ligands
  • Models, Biological*
  • Neuregulin-1 / pharmacology
  • Nitriles / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Reproducibility of Results
  • Signal Transduction* / drug effects
  • Wortmannin

Substances

  • Androstadienes
  • Butadienes
  • Ligands
  • Neuregulin-1
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • U 0126
  • Epidermal Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Wortmannin