Positive and negative regulation of I kappa B kinase activity through IKK beta subunit phosphorylation

I kappa B [inhibitor of nuclear factor kappa B (NF-kappa B)] kinase (IKK) p hosphorylates I kappa B inhibitory proteins, causing their degradation and activation of transcription factor NF-KB, a master activator of inflammator y responses. IKK is composed of three subunits-IKK alpha and IKK beta, whic h are highly similar protein kinases, and IKK gamma, a regulatory subunit. In mammalian cells, phosphorylation of two sites at the activation Loop of IKK beta was essential for activation of IKK by tumor necrosis factor and i nterleukin-1. Elimination of equivalent sites in IKK alpha, however, did no t interfere with IKK activation. Thus, IKK beta, not IKK alpha, is the targ et for proinflammatory stimuli. Once activated, IKK beta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.