Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 3, Pages E326-E333Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314446111
Keywords
cell sensing; MAPK signaling; mutual information; ultrasensitivity; biomolecular networks
Categories
Funding
- Medical Research Council Fellowship in Biomedical Informatics
- Biotechnology and Biological Sciences Research Council [JO14699/1]
- Medical Research Council [G0901763]
- BBSRC [BB/J014699/1] Funding Source: UKRI
- EPSRC [EP/D063485/1] Funding Source: UKRI
- MRC [G0901763] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J014699/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1098791, EP/D063485/1] Funding Source: researchfish
- Medical Research Council [G0901763] Funding Source: researchfish
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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.
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