IκB kinase complexes: gateways to NF-κB activation and transcription

Inhibitors of NF-κB signaling: 785 and counting

“…Therefore, the identification of specific and potent inhibitors of NF-kB has been the goal of many researchers and pharmaceutical companies. Due to the large number of inducers of NF-kB (Pahl, 1999;www.nf-kb.org) and the various levels of regulation of this pathway (Perkins, 2006;Scheidereit, 2006), inhibitors include a wide variety of molecules that act at any of several levels in the pathway.…”

“…The phosphorylation and degradation of IkB have received great attention as key steps for the regulation of NF-kB complexes (see Scheidereit, 2006). The IkB kinase (IKK) complex contains two kinase subunits, IKKa and IKKb, and an associated scaffold-like regulatory protein called NEMO (aka IKKg).…”

“…IKKa and b share much sequence similarity and can form homoand heterodimers. After stimulation of cells by agents such as tumor necrosis factor a (TNFa), interleukin-1 (IL-1) or various pathogens, the IKK complex is activated in part by phosphorylation of specific serine residues in the activation loop of each IKK subunit (see Scheidereit, 2006). The activated IKK complex can then phosphorylate IkB on two serine residues (Ser 32 and 36 in human IkBa).…”

“…The two most common pathways are the canonical (or classical) and the non-canonical (or alternative) pathways (Gilmore, 2006;Scheidereit, 2006). In the canonical pathway, a complex such as p50-RelA/IkBa is activated by an IKK complex containing IKKa/IKKb/NEMO, with IKKb being the primary kinase for IkBa.…”

“…Furthermore, IKKa and IKKb can be activated independently by different upstream signals. Moreover, the IKKs can phosphorylate substrates in addition to the IkBs (Scheidereit, 2006). Similarly, the different IkB proteins have different affinities for the diverse NF-kB dimers.…”