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

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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 suggest 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. A cell is subjected to constantly changing environments and time-varying stimuli. Signals sensed at the cell surface are transmitted inside the cell by signaling pathways. Such pathways can transform signals in diverse ways and perform some preliminary information processing. A ubiquitous building block of signaling pathways is a simple biochemical cycle involving covalent modification of an enzyme–substrate pair. Our paper is devoted to fully characterizing the static and dynamic behavior of this simple cycle, an essential first step in understanding the behavior of interconnections of such cycles. It is known that a signaling cycle can function as a static switch, with the steady-state output being an “ultrasensitive” function of the input, i.e., changing from a low to high value for only a small change in the input. We show that there are in fact precisely four major regimes of static and dynamic operation (with ultrasensitive being one of the static regimes). Each regime has its own input–output characteristics. Despite the distinctive features of these four regimes, they all respond to time-varying stimuli by filtering out high-frequency fluctuations or noise in their inputs, while passing through the lower-frequency information-bearing variations. A cell can select the regime and tune the noise-filtering characteristics of the individual cycles in a specific signaling pathway. This tunability makes signaling cycles versatile components of elaborate cell-signaling pathways.
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