Abstract
Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. Such high variation is beneficial for population‐level regulation of cell functions but abolishes accurate single‐cell signal transmission. Here, we measure cell‐to‐cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5–15%, compatible with accurate single‐cell transmission. Focusing on bimodal ERK signaling, we show that variation and covariation in MEK and ERK expression improves controllability of the percentage of activated cells, demonstrating how variation and covariation in expression enables population‐level control of binary cell‐fate decisions. Together, our study argues for a control principle whereby low expression variation enables accurate control of analog single‐cell signaling, while increased variation, covariation, and numbers of pathway components are required to widen the stimulus range over which external inputs regulate binary cell activation to enable precise control of the fraction of activated cells in a population.
Highlights
Vertebrate signaling has been shown to control both binary and analog outputs
We assumed that each of these components has “expression variation,” meaning that their concentrations vary between cells with a coefficient of variation (CV) calculated as their standard deviation divided by their mean value in the cell population
For a higher CV of 10%, the signaling responses to a threefold increase in R partially overlap with the unstimulated cell responses, and only the responses to a ninefold increase in R can be unequivocally distinguished from unstimulated cell responses
Summary
Vertebrate signaling has been shown to control both binary and analog outputs. Here, we use the term binary if the output is bimodal and the term analog if the output signal changes in parallel with the input signal without bifurcations during the transmission. Analog signaling is needed to accurately regulate the timing or duration of intermediate cell processes such as in the cell cycle where the time between the start of S-phase to mitosis has only small variation between individual cells (Spencer et al, 2013). Such precise regulation of durations requires low noise in the signaling steps before mitosis (Kar et al, 2009). Together, these examples suggest that accurate analog signaling is important for graded control of cell outputs in single cells as well as for accurate internal timing
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