Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signalling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability of cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the mitogen-activated protein kinase Fus3 mediates fast-acting negative feedback that adjusts the dose response of the downstream system response to match the dose response of receptor-ligand binding. This ‘dose–response alignment’, defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a previously uncharacterized signal-promoting function of the regulator of G-protein signalling protein Sst2. Our work suggests that negative feedback is a general mechanism used in signalling systems to align dose responses and thereby increase the fidelity of information transmission.
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We thank P. Abola, S. Andrews, A. Arkin, M. Bowen, L. Buck, C. Denby, A. Gann, D. Meldrum, T. Mitchison, C. Pabo, M. Ptashne, M. Reese, O. Resnekov, C. Ryan, M. Snyder, T. Thomson, A. E. Tsong and M. Wilson for discussions and/or comments on the manuscript, and O. Resnekov for help in articulating the requirements for fluidic induction devices. Work, including that of M.H. at the University of Washington, was supported by the Alpha Project at the Center for Quantitative Genome Function, an NIH Center of Excellence in Genomic Science under grant P50 HG02370 from the National Human Genome Research Institute to R.B.
Author Contributions R.C.Y. performed the Ste5 translocation, loss of G-protein and Dig1–Ste12 FRET, MAP kinase phosphorylation, mRNA measurements, and the image-based measurements of system output. C.G.P. and A.G. noted and helped articulate the relationship of negative feedback to dose–response overlap. C.G.P. and R.C.Y. performed flow cytometric measurements. L.L. and A.G. contributed to discussions about mutual information calculations and analysis. R.C.Y. and A.G. performed data analysis on loss of FRET experiments. A.C.-L. and A.G. carried out extensive initial measurements of Ste5 recruitment. K.B. provided unpublished information about protein quantification useful in initial discussions about dose–response alignment. R.C.Y. and D.P. performed numerous measurements verifying protein abundance in other strains. E.S. constructed the inhibitor-sensitive fus3-as2 and kss1-as2 alleles. M.H. designed and built fluidic devices used to induce the system in response to articulated requirements. R.B. provided input into project direction, experimental design and interpretation of results. R.C.Y., C.G.P. and R.B. wrote the paper and guarantee the integrity of the results.
This file contains Supplementary Methods and Data, Supplementary Tables S1-S4 and S6, Supplementary Figures and Legends S1-S14 and Supplementary References
About this article
Nature Communications (2016)