Shared pathways of I kappa B kinase-induced SCF beta TrCP-mediated ubiquitination and degradation for the NF-kappa B precursor p105 and I kappa B alpha

p105 (NFKB1) acts in a dual way as a cytoplasmic I kappaB molecule and as t he source of the NF-kappaB p50 subunit upon processing. p105 can form vario us heterodimers with other NF-kappaB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the I kappaB kinase (Ik;Ii) complex invokes p105 degradation and p50 homod imer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKK beta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site lo cated in a death domain, which is separate from the substrate site. The sub strate 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 DSG Psi motif and is functionally most critical. The region containing both ser ines is homologous to the N-terminal destruction box of I kappaB alpha, -be ta, and -epsilon. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubi quitin ligase substrate recognition molecules beta TrCP1 and beta TrCP2, re sulting in polyubiquitination and complete degradation by the proteasome. H owever, processing of p105 is independent of IKK signaling. In line with th is and as a physiologically relevant model, lipopolysaccharide (LPS) induce d degradation of endogenous p105 and p50 homodimer formation, but not proce ssing in pre-B cells. In mutant pre-B cells lacking IKK gamma, processing w as unaffected, but LPS-induced p105 degradation was abolished. Thus, a func tional endogenous IKK complex is required for signal-induced p105 degradati on but not for processing.