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Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation--that is, dynamics--to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2+)), and nuclear factor kappa-B (NF-κB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks., (Copyright © 2014, American Association for the Advancement of Science.)

Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether oscillatory behavior is the basis for a signaling code based on frequency modulation (FM) or whether the negative feedback control modules have evolved to fulfill other functional requirements. Here, we use experimentally calibrated computational models to interrogate the negative feedback loops that regulate the dynamic activity of the transcription factor NF-κB. Linear stability analysis of the model shows that oscillatory frequency is a hard-wired feature of the primary negative feedback loop and not a function of the stimulus, thus arguing against an FM signaling code. Instead, our modeling studies suggest that the two feedback loops may be tuned to provide for rapid activation and inactivation capabilities for transient input signals of a wide range of durations; by minimizing late phase oscillations response durations may be fine-tuned in a graded rather than quantized manner. Further, in the presence of molecular noise the dual delayed negative feedback system minimizes stochastic excursions of the output to produce a robust NF-κB response.

Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation--that is, dynamics--to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2+)), and nuclear factor kappa-B (NF-κB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.