p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the 
source of the NF-kappaB p50 subunit upon processing. p105 can form various 
heterodimers with other NF-kappaB subunits, including its own processing 
product, p50, and these complexes are signal responsive. Signaling through the 
IkappaB kinase (IKK) complex invokes p105 degradation and p50 homodimer 
formation, involving p105 phosphorylation at a C-terminal destruction box. We 
show here that IKKbeta phosphorylation of p105 is direct and does not require 
kinases downstream of IKK. p105 contains an IKK docking site located in a death 
domain, which is separate from the substrate site. The substrate residues were 
identified as serines 923 and 927, the latter of which was previously assumed to 
be a threonine. S927 is part of a conserved DSGPsi motif and is functionally 
most critical. The region containing both serines is homologous to the 
N-terminal destruction box of IkappaBalpha, -beta, and -epsilon. Upon 
phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate 
recognition molecules betaTrCP1 and betaTrCP2, resulting in polyubiquitination 
and complete degradation by the proteasome. However, processing of p105 is 
independent of IKK signaling. In line with this and as a physiologically 
relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 
and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B 
cells lacking IKKgamma, processing was unaffected, but LPS-induced p105 
degradation was abolished. Thus, a functional endogenous IKK complex is required 
for signal-induced p105 degradation but not for processing.