Cell-to-cell variability of cascades with a localized switch at the terminal level.

<p><b>A</b> Simulations show that pronounced variability for both (defined as the stimulus for a half-maximal pathway activation) and . The concepts and parameter values correspond to <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003357#pcbi-1003357-g001" target="_blank">Figure 1B</a>, and the simulations were performed by iteratively applying Eqs. 16 and 17 with a Hill coefficient (Supplemental <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003357#pcbi.1003357.s010" target="_blank">Table S1</a>). Colored box plots represent the and distribution of the ultrasensitive model, while gray box plots show the behavior of the reference gradual cascade (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003357#pcbi-1003357-g001" target="_blank">Figure 1B</a>). <b>B</b> The variabilities of a cascade with a localized switch at the terminal level were analyzed using the IQRatio, and the activation resistance was tuned by varying several phosphatase rate constants (– , thick, solid lines), and compared to a gradual model (thin, dashed lines). In contrast to a cascade with distributed ultrasensitivity (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003357#pcbi-1003357-g003" target="_blank">Figure 3D</a>), homogeneous switching of all cells at a defined stimulus value is not possible even for low activation resistances. Similar results are obtained using the coefficient of variation as a measure of variability (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003357#pcbi.1003357.s004" target="_blank">Figure S4</a>).