A functional map of NFκB signaling identifies novel modulators and multiple system controls

BACKGROUND: The network of signaling pathways that leads to activation of the NFκB transcription factors is a branched structure with different inputs and cross-coupling with other signaling pathways. How these signals are integrated to produce specific, yet diverse responses is not clearly understood. To identify the components and structural features of the NFκB network, a series of cell-based, genomic screens was performed using a library of approximately 14,500 full-length genes. RESULTS: A total of 154 positive and 88 negative modulators of NFκB signaling were identified. Using a series of dominant-negative constructs and functional assays, these modulators were mapped to the known NFκB signaling cascade. Most of the positive modulators acted upstream of the IκB kinase complex, supporting previous observations that the IκB kinases represent the primary point of convergence in the network. A number of negative modulators were localized downstream of the IκB kinase β (IKBKB) subunit, suggesting that they form an additional layer of negative control within the system. The expression of the modulators at the RNA level was distributed disproportionately across tissues, providing flexibility in network structure, and the number of positive and negative modulators present in a given tissue was highly correlated, suggesting that positive and negative regulation is balanced at the tissue level. CONCLUSION: The relative locations of the modulators are consistent with an hourglass structure for the NFκB network that is characteristic of robust systems. The tissue distribution of the modulators and downstream location of the negative modulators serve as layers of control within the system that allow differential responses to different stimuli.