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

Abstract

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.

Construction of multicellular yeast networks using the communication toolkit with variable specificity and attenuation

“…Although the constitutive promoter RPL18B also exhibited increased promoter activity, most likely an artifact due to increase in size of the αfactor stimulated cells, this increase was much weaker compared to the other promoters. Sensitivity to α-factor has also shown several-fold difference, with lowest EC50 observed for SST2 promoter and highest EC50 for MSG5 promoter, consistent with previous observations 28 (Supplementary Table 1). Selection of sender, receiver and suppressor parts.…”

“…1). As response parts, we selected seven promoters of S. cerevisiae genes that are known to be regulated in response to the pheromone-induced activation of the mating signaling pathway 28 . mfα1 genes that encode α-factors and their corresponding Ste2 GPCRs from several different Saccharomycotina species were selected as sender and receiver parts, respectively.…”

“…Characterization of response parts. The set of pheromone-inducible promoters of S. cerevisiae genes was selected to cover different expression strengths and profiles, based on RNA sequencing data for S. cerevisiae MATa cells stimulated with different doses of α-factor 28 . To characterize response characteristics of these promoters controlling expression of fluorescent reporter Venus, we constitutively preprint (which was not certified by peer review) is the author/funder.…”

Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis

“…For example, positive feedback loops facilitate adequate signal amplification, while negative feedback loops enable rapid, tightly regulated responses to stimuli and prevent pathway hyperactivation ( Cheong and Levchenko, 2010 ; Tyson et al, 2003 ). Negative feedback also ensures that signalling pathways are resistant to external perturbations ( Stelling et al, 2004 ) and may optimise the energetic cost of signal transduction ( Anders et al, 2020 ). Identifying and characterising feedback mechanisms in signal transduction pathways is pivotal since dysfunctional cell signalling frequently underlies complex diseases ( Fazakerley et al, 2019 ; Mora-Garcia and Sakamoto, 1999 ; Nguyen and Kholodenko, 2016 ).…”

Sensitivity minimization, biological homeostasis and information theory

“…Recently, Anders et al. ( 2020 ) used the FIM to demonstrate how the MAPK signaling cascade balances energetic costs against the accuracy of information transmission in budding yeast. Relations between the FIM and Bode’s integral are presented in Liu and Elia ( 2014 ).…”