The NF-kappaB/Rel transcription factors are present in the cytosol in an inactive state complexed with the inhibitory IkappaB proteins. Activation of IkappaBalpha occurs through both serine and tyrosine phosphorylation events. Activation through phosphorylation at Ser-32 and Ser-36 is followed by proteasome-mediated degradation, resulting in the release and nuclear translocation of active NF-kappaB. This pathway of IkappaBalpha regulation occurs in response to various NF-kappaB-activating agents, such as TNFalpha, interleukins, LPS, and irradiation. An alternative pathway for IkappaBalpha regulation occurs through tyrosine phosphorylation of Tyr-42 and Tyr-305. Tyr-42 is phosphorylated in response to oxidative stress and growth factors. This phosphorylation can lead to degradation of IkappaBalpha and NF-kappaB-activation. In contrast, Tyr-305 phosphorylation by c-Abl has been implicated in IkappaBalpha nuclear translocation and inhibition of NF-kappaB-activation. Thus, tyrosine phosphorylation of IkappaBalpha may be an important regulatory mechanism in NF-kappaB signaling.
