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

Abstract

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.