Figure 5
From: Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity
Varying a single parameter value can produce a large change in the off-target response. Stimulus response curves were plotted for the n = 3 network using a randomly selected parameter set and a parameter set derived from a Xenopus model [18] (all parameters values are listed in Table 2). For each parameter set, E 2 and K 3 were increased or decreased by 1 order of magnitude and the resulting stimulus response curves were plotted. (A-B) The random parameter set produced an off-target effect in Y2 of 0.40 (data not shown) and in Y2* of 0.19. (A) Increasing E 2 from 32.56 to 325.61 substantially decreased the off-target effect in Y2*, while decreasing E 2 to 3.26 increased the off-target effect in Y2* to 0.27. (B) Increasing K 3 from 0.04 to 0.41 reduced the response in Y2* below the detection threshold to 0.07, while decreasing K 3 to 0.004 increased the off-target response to 0.26. (C-D) A second parameter set was derived from the literature using MAPK parameters from a Xenopus model. This parameter set did not initially produce an off-target effect because the response in both Y2* and Y2 was 0.08, which was below the detection threshold. (C) Increasing or decreasing E 3 to 0.025 or 0.00025, respectively, from 0.0025 had no effect on the response to the targeted inhibitor. (D) In contrast, increasing K 3 from 0.25 to 2.5 eliminated the original response completely, while decreasing K 3 from 0.25 to 0.025 produced a large off-target response of 0.60. Original parameter values prior to variation are indicated by ‡ on the plots (see also Table 2).