Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses.
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.
Birtwistle
Marc R
MR
Department of Chemical Engineering, University of Delaware, Newark, DE, USA.
Hatakeyama
Mariko
M
Yumoto
Noriko
N
Ogunnaike
Babatunde A
BA
Hoek
Jan B
JB
Kholodenko
Boris N
BN
D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D020890:Neuregulin-1 / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D008024:Ligands; D020890:Neuregulin-1; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077191:Wortmannin