The regulatory logic of the NF-kappaB signaling system.

NF-kappaB refers to multiple dimers of Rel homology domain (RHD) containing polypeptides, which are controlled by a stimulus-responsive signaling system that mediates the physiological responses to inflammatory intercellular cytokines, pathogen exposure, and developmental signals. The NF-kappaB signaling system operates on transient or short timescales, relevant to inflammation and immune responses, and on longer-term timescales relevant to cell differentiation and organ formation. Here, we summarize our current understanding of the kinetic mechanisms that allow for NF-kappaB regulation at these different timescales. We distinguish between the regulation of NF-kappaB dimer formation and the regulation of NF-kappaB activity. Given the number of regulators and reactions involved, the NF-kappaB signaling system is capable of integrating a multitude of signals to tune NF-kappaB activity, signal dose responsiveness, and dynamic control. We discuss the prevailing mechanisms that mediate signaling cross talk.