Expression variation and covariation impair analog and enable binary signaling control.

Area of Science:

• Cellular Biology
• Systems Biology
• Quantitative Proteomics

Background:

• Cellular signaling proteins typically exhibit high variability (approx. 25% CV) due to synthesis and degradation noise.
• This high variation hinders accurate single-cell signal transmission, despite its benefits for population-level regulation.

Purpose of the Study:

• To quantify cell-to-cell variability in relative protein abundance in individual cells.
• To investigate the role of expression variation and covariation in controlling cell fate decisions, specifically bimodal ERK signaling.

Main Methods:

• Quantitative proteomics was employed to measure relative protein abundance in individual *Xenopus laevis* eggs and cultured human cells.
• Analysis focused on the variability and covariation of MEK and ERK expression in the context of bimodal ERK signaling.

Main Results:

• Measured protein abundance variation was significantly lower than expected, ranging from 5-15% CV, which supports accurate single-cell signal transmission.
• Variation and covariation in MEK and ERK expression were found to enhance the controllability of the percentage of activated cells.
• This demonstrates a mechanism for population-level control of binary cell-fate decisions.

Conclusions:

• Low expression variation enables accurate analog single-cell signaling.
• Increased variation, covariation, and pathway component numbers facilitate population-level control of binary cell-fate decisions by widening the stimulus response range.