Operating Regimes of Signaling Cycles: Statics, Dynamics, and Noise Filtering

TL;DR

This paper systematically analyzes signaling cycles, revealing four operational regimes and demonstrating their ability to act as tunable low-pass filters that can suppress high-frequency noise in cellular signaling.

Contribution

It introduces a comprehensive classification of signaling cycle regimes and highlights their noise-filtering and tunability features, expanding understanding beyond traditional models.

Findings

Four distinct signaling regimes identified with unique input-output behaviors.

Signaling cycles function as tunable low-pass filters for noise reduction.

Analytical results validated by numerical simulations even with large noise amplitudes.

Abstract

A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input-output characteristic in a certain steady-state regime. Here we systematically study the cycle's steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input-output characteristics. These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggests the possibility of signaling cycles operating in one of the new regimes. We then consider the cycle's dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act - in all four regimes - as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell signaling pathways.