The transcription factor NFkB is retained in the cytoplasm in an inactive form by the inhibitory protein IkB. Activation of NFkB requires that IkB be phosphorylated on specific serine residues, which results in targeted degradation of IkB. IkB kinase a (IKKa), previously designated CHUK, interacts with IkB-a and specifically phosphorylates IkB-a on Ser 32 and 36, the sites that trigger its degradation. IKKa appears to be critical for NFkB activation in response to proinflammatory cytokines. Phosphorylation of IkB by IKKa is stimulated by the NFkB inducing kinase (NIK), which itself is a central regulator for NFkB activation in response to TNF and IL-1. The functional IKK complex contains three subunits, IKKa, IKKb and IKKg (also designated NEMO), and each appear to make essential contributions to IkB phosphorylation.
