Crosstalk via the NF-kappaB signaling system

The nuclear factor kappaB (NF-kappaB) family of transcription factors consists of 15 possible dimers whose activity is controlled by a family of inhibitor proteins, known as IkappaBs. A variety of cellular stimuli, many of them transduced by members of the tumor necrosis factor receptor (TNFR) superfamily, induce degradation of IkappaBs to activate an overlapping subset of NF-kappaB dimers. However, generation and stimulus-responsive activation of NF-kappaB dimers are intimately linked via various cross-regulatory mechanisms that allow crosstalk between different signaling pathways through the NF-kappaB signaling system. In this review, we summarize these mechanisms and discuss physiological and pathological consequences of crosstalk between apparently distinct inflammatory and developmental signals. We argue that a systems approach will be valuable for understanding questions of specificity and emergent properties of highly networked cellular signaling systems.