Integrating cell-signalling pathways with NF-κB and IKK function

Key Points The nuclear factor (NF)-κB, inhibitor of NF-κB (IκB) and IκB kinase (IKK) pathway is activated in response to various stimuli in many cell types. NF-κB is activated by many mechanisms, including the canonical pathway, which activates the IKK complex and results in the degradation of IκB in response to inflammatory stimuli. Several NF-κB- and IκB-independent substrates for the IKK proteins are now being identified. These indicate that in addition to induction of NF-κB, these kinases might function to programme the overall cellular response to specific activating stimuli. The consequences of NF-κB activation can vary depending on the context in which activation occurs. This modulation is at least in part due to the regulation of NF-κB subunits in the nucleus, where they translocate after release from cytoplasmic IκB proteins. One mechanism of regulating NF-κB subunit function is through post-translational modifications such as phosphorylation and acetylation. This allows other cell-signalling proteins to influence NF-κB function and therefore serves as a mechanism to integrate their activities with the NF-κB and IKK pathway. NF-κB subunits can also bind DNA cooperatively and activate transcription synergistically with heterologous transcription factors. As independent cell-signalling pathways regulate many of these factors, this provides another mechanism through which NF-κB and IKK activity can be integrated with the overall cellular response to multiple stimuli. Feedback loops exist in which the activation of NF-κB target genes can influence the later time points of the NF-κB response to specific cell stimuli. Crosstalk with the Jun N-terminal kinase (JNK), p53 and nuclear-receptor pathways provide specific examples of the diversity of mechanisms that exist to link NF-κB function to other important networks that regulate cell fate, the immune response and inflammation. The complexity of the mechanisms regulating NF-κB function presents both a challenge and an opportunity when seeking to exploit NF-κB function in a clinical setting. Results indicate that care must be taken when using NF-κB or IKK inhibitors in the clinic, but they also indicate that understanding these pathways will improve diagnostic capabilities and maximize the effectiveness of such inhibitors. Rather than functioning in isolation, the activities of nuclear factor (NF)-κB and inhibitor of NF-κB kinase (IKK) proteins are integrated with diverse cell-signalling pathways, includi