Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. I will discuss two recent projects from the lab that analyzed mechanism utilized by cells to mitigate noise-induced information loss. In the first project, 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. In the second project, we investigated how cells utilize cell to cell communication to reduce the effects of noise using epidermal growth factor receptor (EGFR) transactivation that results from extracellular ATP, a key damage signal critical for wound response signaling. We show that ectodomain shedding results in paracrine communication that reduces the variability of pathways downstream of EGFR. Analysis of cellular response fidelity as a function of the paracrine communication distance showed that the experimentally measured communication distance maximizes the reliability of wound response signals. Our results demonstrate that local paracrine communication can be used to filter out response noise through local averaging and that this noise filtering can be optimized by regulating paracrine communication distance.
About the Speaker
Faculty Host: Robin Lee