Fig. 1. Kinetic scheme for EGFR signaling (adapted from Kholodenko et al., 1999).

Fig. 2. Evolution of concentration profiles when phosphorylation reaction (3) alone is targeted by kinase inhibitors (ζ₆=ζ₁₄=1). While the inhibitor has a significant effect on the target node itself (the receptor phosphorylation, top left), the signals further downstream in the network are much less sensitive to the inhibitor, with doses less than IC₅₀ generally having an insignificant effect.

Fig. 3. Evolution of concentration profiles when phosphorylation reactions (3) and (14) are simultaneously targeted by kinase inhibitors (ζ₆=1). Although the administration of the second inhibitor has an imperceptible effect on nodes in unrelated parts of the network from the target node ([R–G–S] and [R–PLP], bottom row), the [R–Sh–G–S] profile exhibits a pronounced reduction since this signal is downstream of the serially-connected target nodes.

Fig. 4. Evolution of concentration profiles when phosphorylation reactions (3) and (6) are simultaneously targeted by kinase inhibitors (ζ₁₄=1). Although the administration of the second inhibitor has an imperceptible effect on nodes in unrelated parts of the network from the target node ([R–G–S] and [R–Sh–G–S]), the [R–PLP] profile exhibits a pronounced reduction, since this signal is downstream of the serially-connected target nodes.

Fig. 5. A comparison of several signals downstream of two serially-connected target nodes with the corresponding hypothetical additive effects of targeting the same nodes individually. In each case, the signal amplitude is considerably smaller than the predicted additive signal, which demonstrates that targeting serially-connected processes has a synergistic effect on downstream signal attenuation.

Fig. 6. The extent of feedback and/or cross-talk between the receptor cycle initiated by the binding of PLC and the other receptor cycles in the EGFR network. Here, reaction (6) alone has been inhibited. Plots on the right are enlargements of portions of the corresponding plots on the left.

Fig. 7. The extent of feedback and/or cross-talk between the receptor cycle initiated by the binding of Shc and the other receptor cycles in the EGFR network. Here, reaction (14) alone has been inhibited. Plots on the right are enlargements of portions of the corresponding plots on the left.