School of Computing Research Colloquia

Information transfer by leaky, heterogeneous, protein kinase signaling systems

Margaritis Voliotis, School of Mathematics, University of Bristol

Abstract: Cells must sense extracellular signals and transfer the information contained about their environment reliably to make appropriate decisions. To perform these tasks, cells use signal transduction networks that are subject to various sources of noise, such as cell-to-cell variability in the componentry of the network and basal activity (the propensity for activation of the network output in the absence of the signal of interest). Basal activity is widespread in signaling systems under physiological conditions, has phenotypic consequences, and is often raised in disease. We combine theory and experiment to study how basal activity and heterogeneity of network componentry affect information transfer by cell signaling systems. First, using theoretical models of protein kinase signaling, we show that negative feedback makes information transfer by the system robust against the combined effect of the two types of noise. We verify our theoretical predictions in an experimental study of ERK signaling by single cells with heterogeneous ERK expression levels. In particular, we find that negative feedback substantially increases information transfer to the nucleus by (i) preventing a near-flat average response curve due to basal network activity and (ii) reducing sensitivity to variation in substrate expression levels. Our results reveal an important role for negative feedback mechanisms in protecting the information transfer function of saturable, heterogeneous cell signaling systems from basal activity.