How robust are switches in intracellular signaling cascades?

Since all-or-none decisions of the cell are controlled by extracellular signals, cells have biochemical switches within their intracellular signaling networks. Central elements of these switches are multisite phosphorylation, enzymic saturation, and amplification by cascades. Moreover, positive feedback can contribute to switch-like behavior termed also ultrasensitivity. Here we analyse the robustness of these mechanisms exemplified by models of the three-molecule MAPK-cascade and the single-molecule Goldbeter-Koshland switch. We show that the ultrasensitivity in the MAPK-cascades is more robust against changes of the kinetic parameters than the Goldbeter-Koshland switch. If multiple parameters are changed randomly, the effects of parameter changes can compensate each other in the cascade leading to a remarkable robustness of the switch-like behavior. The different degrees of robustness can be traced back to the different mechanisms of generating ultrasensitivity. While in the Goldbeter-Koshland switch the saturation of the enzymes are crucial, in the MAPK-cascade the adjustment of working ranges determines the ultrasensitivity. Our results indicate that amplification of ultrasensitivity in cascades and multisite phosphorylation might be a design principle to achieve robust switches. (C) 2003 Elsevier Ltd. All rights reserved.