Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyze the ability of temporal signal modulation, that is dynamics, to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca2+), and nuclear factor kappa-B (NFκB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to non-dynamic 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 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.

Toll-like receptors (TLRs) recognize specific pathogen-associated molecular patterns and initiate innate immune responses through signaling pathways that depend on the adaptor proteins MyD88 (myeloid differentiation marker 88) or TRIF (TIR domain-containing adaptor protein-inducing interferon-β). TLR4, in particular, uses both adaptor proteins to activate the transcription factor nuclear factor κB (NF-κB); however, the specificity and redundancy of these two pathways remain to be elucidated. We developed a mathematical model to show how each pathway encodes distinct dynamical features of NF-κB activity and makes distinct contributions to the high variability observed in single-cell measurements. The assembly of a macromolecular signaling platform around MyD88 associated with receptors at the cell surface determined the timing of initial responses to generate a reliable, digital NF-κB signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-κB signals through TRIF. With iterative mathematical model development, we predicted the molecular mechanisms by which the MyD88- and TRIF-mediated pathways provide ligand concentration-dependent signaling dynamics that transmit information about the pathogen threat.