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

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) HRGinduced 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.

Biology using engineering tools

“…Modelling reveals, however, that negative feedback to receptors can have competing effects, as receptors are responsible for the recruitment of both positive and negative effectors of ERK signaling. 47 Thus, the classification of such feedback as strictly "negative" or "positive" is likely to be context-dependent.…”

“…68 Nevertheless, with ten-fold increases in growth factor dose leading to linear increases in ppERK. 10,47,[60][61][62] One possible explanation for this is variable amplification of the growth factor signal into ppERK signals as a function of growth factor dose. 62 Analysis of a network model for how ErbB receptors lead to activation of ERK through Ras suggested that the control of this variable amplifier strength lies with the amount of active Ras, the Raf-MEK association rate and the MEK dephosphorylation rate.…”

“…In some cases, there is a linear relationship between the levels of active (tyrosine phosphorylated) receptor and ppERK levels. 47,60 In such cases, R* may be taken as a surrogate for ppERK levels. It was reported that n = 0.31 for EGF binding to EGFR, 63 and plotting Eq.…”

Classic and contemporary approaches to modeling biochemical reactions

“…3C). Parameters for this solution derive from published models of receptor-mediated phosphorylation of the Shc adaptor protein by epidermal growth factor receptor (Birtwistle et al 2007;Chen et al 2009). In this case, separable early/fast and late/slow phase solutions can be defined (Supplemental Eqs.…”

“…Under the conditions shown in Figure 3C, the With these considerations in mind, we might ask what subset of elementary biochemical reactions in cells are reasonably approximated by Michaelis-Menten kinetics. In the case of the signal transduction networks currently being studied using kinetic modeling, the conclusion appears to be that few if any reactions can be so approximated, even though many can be described quite well by a mass action dynamical system (Chen et al 2000(Chen et al , 2009Birtwistle et al 2007;Albeck et al 2008). The observed mismatch does not involve an absence of well-mixed compartments or the stochastic nature of cellular biochemistry (although both are true), but the very limited range of parameter values over which the MichaelisMenten approximation holds.…”