title: Information transfer by leaky, heterogeneous, protein kinase signaling systems.
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. Here, we study the effects on information transfer of two particular types of noise: basal (leaky) network activity and cell-to-cell variability in the componentry of the network. Basal activity is the propensity for activation of the network output in the absence of the signal of interest. We show, using theoretical models of protein kinase signaling, that the combined effect of the two types of noise makes information transfer by such networks highly vulnerable to the loss of negative feedback. In an experimental study of ERK signaling by single cells with heterogeneous ERK expression levels, we verify our theoretical prediction: In the presence of basal network activity, negative feedback substantially increases information transfer to the nucleus by both preventing a near-flat average response curve and reducing sensitivity to variation in substrate expression levels. The interplay between basal network activity, heterogeneity in network componentry, and feedback is thus critical for the effectiveness of protein kinase signaling. Basal activity is widespread in signaling systems under physiological conditions, has phenotypic consequences, and is often raised in disease. 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.
authors.affiliation: School of Mathematics and Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TW, United Kingdom.
authors.forename: Margaritis
authors.initials: M
authors.lastname: Voliotis
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Perrett
authors.forename: Chris
authors.initials: C
authors.lastname: McWilliams
authors.forename: Craig A
authors.initials: CA
authors.lastname: McArdle
authors.forename: Clive G
authors.initials: CG
authors.lastname: Bowsher
mesh_terms: D001499:Bayes Theorem; D002467:Cell Nucleus / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D015999:Multivariate Analysis; D010641:Phenotype; D010766:Phosphorylation
chemical_list: D008024:Ligands; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK signaling; biomolecular networks; cell sensing; mutual information; ultrasensitivity