The IκB kinase complex: master regulator of NF-κB signaling

The Nuclear Factor-kappa B (NF-kappa B) family of transcription factors regulates the expression of a wide range of genes critical for immune and inflammatory responses, cell survival, immune development, and cell proliferation. Dysregulated NF-kappa B activity occurs in a number of chronic inflammatory diseases and certain types of cancers making NF-kappa B signaling an attractive target for the development of anti-inflammatory and anti-cancer drugs. A pivotal regulator of all inducible NF-kappa B signaling pathways is the I kappa B kinase (IKK) complex that consists of two kinases (IKK alpha and IKK beta) and a regulatory subunit named NF-kappa B essential modulator (NEMO). Genetic analysis of the IKK complex has identified two separate pathways named the classical and non-canonical mechanisms that are dependent on either NEMO and IKK beta (classical) or IKK alpha alone (non-canonical). To better understand the mechanisms that regulate IKK complex activity and to address the differential functions of IKK alpha and IKK beta we have molecularly dissected the IKKs. We describe here how these studies have identified a unique inhibitor of pro-inflammatory NF-kappa B signaling, an unforeseen role for IKK alpha in the classical NF-kappa B pathway, and a novel functional domain in IKK beta that is not present in IKK alpha.