Resistance to signal activation governs design features of the MAP kinase signaling module.

Given its broad influence over numerous cell functions, redesigning the mitogen-activated protein (MAP) kinase signaling module would offer a powerful means to engineer cell behavior. Early challenges include identifying quantitative module features most relevant to biological function and developing simple design rules to predictably modify these features. This computational study delineates how features such as signal amplification, input potency, and dynamic range of output may be tuned by manipulating chief module components. Importantly, the model construction identifies a metric of resistance to signal activation that quantitatively predicts module features and design trade-offs for broad perturbations in kinase and phosphatase expression. Its predictive utility extends to dynamic properties such as signal lifetime, which often dictates MAP kinase effect on cell function. Taken together, we propose that predictably altering MAP kinase signaling by tuning resistance is not only a feasible engineering strategy, but also one exploited by natural systems to allow each MAP kinase to exert pleiotropic effects in a context-dependent manner. External stimuli not only activate kinases, but also alter phosphatase expression and activity, thereby reconfiguring a single module for quantitatively distinct modes of signaling such as transient vs. sustained dynamics, each with unique effects on cell function.