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.
Recommended CitationBirtwistle, Marc R; Hatakeyama, Mariko; Yumoto, Noriko; Ogunnaike, Babatunde A; Hoek, Jan B.; and Kholodenko, Boris N. PhD, DSci, "Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses." (2007). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 139.