Validation of the MEC model against known cellular phenomena.

<p>A) EGF-dependent stimulation of survival signals via activation of Akt. B) Activation of Erk by EGF <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Roux1" target="_blank">[52]</a>. Although a positive relationship between Erk and the ligand can be seen, the activation Erk by EGF seems to exhibit a more complex dynamics than the ones seen in the other diagrams (<i>i.e.</i>, the positive relationship is exhibited when EGF activity levels are 0–40%). This is, however, not surprising given the complex interactions and cross-communication within the ErbB signaling family. C) Activating mutations of known protooncogenes such as Ras result in growth factor-independent activation of Erk <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Sridhar1" target="_blank">[53]</a>. D) Erk dependency on signaling via integrins by extracellular matrix (ECM) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Edin1" target="_blank">[54]</a>. E and F) Activation of Rac and Cdc42 by ECM <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Price1" target="_blank">[55]</a>. G) Positive relationship between Adenylyl Cyclase (AC) and the G-Protein Coupled Receptor ligand alpha-s <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Selbie1" target="_blank">[56]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Milligan1" target="_blank">[57]</a>. H) Hierarchy of ErbB receptor dimerization. The panel on the left represents a system with EGFR expression alone and, thus, the formation of EGFR homodimers. The expression of ErbB2 (middle panel) results in the shift of the formation (activity) from EGFR homodimers (EGFR-EGFR) to the formation of EGFR-ErbB2 heterodimers. Furthermore, the expression of ErbB 1–3 results in the dominant formation of ErbB2–3 heterodimers <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Wiley1" target="_blank">[13]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061757#pone.0061757-Tzahar1" target="_blank">[35]</a>. Note that the references refer to classical, qualitative input-output relationships (not necessarily quantitative dose–response curves), and the dose-response curves presented here are intended to demonstrate how the computational model qualitatively reproduces the referenced input-output relationships over a range of stimulus signals.