Cross-talk and decision making in MAP kinase pathways.

Cells must respond specifically to different environmental stimuli in order to survive. The signal transduction pathways involved in sensing these stimuli often share the same or homologous proteins. Despite potential cross-wiring, cells show specificity of response. We show, through modeling, that the physiological response of such pathways exposed to simultaneous and temporally ordered inputs can demonstrate system-level mechanisms by which pathways achieve specificity. We apply these results to the hyperosmolar and pheromone mitogen-activated protein (MAP) kinase pathways in the yeast Saccharomyces cerevisiae. These two pathways specifically sense osmolar and pheromone signals, despite sharing a MAPKKK, Ste11, and having homologous MAPKs (Fus3 and Hog1). We show that in a single cell, the pathways are bistable over a range of inputs, and the cell responds to only one stimulus even when exposed to both. Our results imply that these pathways achieve specificity by filtering out spurious cross-talk through mutual inhibition. The variability between cells allows for heterogeneity of the decisions.

Modularity of MAP kinases allows deformation of their signalling pathways.

Eukaryotic protein kinase pathways have both grown in number and changed their network architecture during evolution. We wondered if there are pivotal proteins in these pathways that have been repeatedly responsible for forming new connections through evolution, thus changing the topology of the network; and if so, whether the underlying properties of these proteins could be exploited to re-engineer and rewire these pathways. We addressed these questions in the context of the mitogen-activated protein kinase (MAPK) pathways. MAPK proteins were found to have repeatedly acquired new specificities and interaction partners during evolution, suggesting that these proteins are pivotal in the kinase network. Using the MAPKs Fus3 and Hog1 of the Saccharomyces cerevisiae mating and hyper-osmolar pathways, respectively, we show that these pivotal proteins can be re-designed to achieve a wide variety of changes in the input-output properties of the MAPK network. Through an analysis of our experimental results and of the sequence and structure of these proteins, we show that rewiring of the network is possible due to the underlying modular design of the MAPKs. We discuss the implications of our findings on the radiation of MAPKs through evolution and on how these proteins achieve their specificity.