Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly 
controlled, which is important for proper function of NF-kappaB. Accordingly, 
constitutive processing of p100, caused by the loss of its C-terminal processing 
inhibitory domain due to nfkappab2 gene rearrangements, is associated with the 
development of various lymphomas and leukemia. In contrast to the physiological 
processing of p100 triggered by NF-kappaB-inducing kinase (NIK) and its 
downstream kinase, IkappaB kinase alpha (IKKalpha), which requires the E3 
ligase, beta-transducin repeat-containing protein (beta-TrCP), and occurs only 
in the cytoplasm, the constitutive processing of p100 is independent of 
beta-TrCP but rather is regulated by the nuclear shuttling of p100. Here, we 
show that constitutive processing of p100 also requires IKKalpha, but not 
IKKbeta (IkappaB kinase beta) or IKKgamma (IkappaB kinase gamma). It seems that 
NIK is also dispensable for this pathogenic processing of p100. These results 
demonstrate a general role of IKKalpha in p100 processing under both 
physiological and pathogenic conditions. Additionally, we find that IKKalpha is 
not required for the nuclear translocation of p100. Thus, these results also 
indicate that p100 nuclear translocation is not sufficient for the constitutive 
processing of p100.