Design of a MAPK signalling cascade balances energetic cost versus accuracy of information transmission

Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) signalling cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the signalling cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular signalling systems.


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April 2018
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Life sciences study design
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Sample size
Microscopy: number of analyzed cells per sample and time point: 300-4,000, limited by cell density and the size of field of view. In order to asses if (minimal) sample size of 300 allows to correctly estimate gene expression (GFP) distribution of the population, we have performed tests on samples with larger cell numbers by repeatedly sampling subsets of n=300 for all used pheromone concentrations. We found that coefficients of variation for means and s.d.'s of these different subsets were smaller than 5% and 7%, respectively. For flow cytometry, cell numbers were in large excess over those numbers (10,000 cells per sample in promoter exchange experiments (Suppl. Fig. 7) and 20,000 cells per sample in growth competition experiments (Suppl. Fig. 13)) Data exclusions Microscopy: Exclusion of upper and lower 3-percentile in each fluorescence channel in order to exclude segmentation artifacts.

Replication
At least two biological replicates. All attempts in replication were successful to reproduce major conclusions. The axis labels state the marker and fluorochrome used (e.g. CD4-FITC).
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All plots are contour plots with outliers or pseudocolor plots.
A numerical value for number of cells or percentage (with statistics) is provided.

Methodology Sample preparation
Yeast cells growing in Synthetic minimal medium, 1:6 diluted in same medium in 96-well plate Instrument LSR Fortessa Special Order flow cytometer (BD Biosciences) Software FACSDiva (BD) for data collection and analysis, R (package flowCore) and Matlab for analysis Cell population abundance Yeast cell abundance in media > 1000 cells/μl. Yeast gate contained more than 80% of total event number.