The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action 
of the ubiquitin-proteasome system; many of the signaling steps are coordinated 
by protein ubiquitination. The end point of this pathway is to induce 
transcription, and to this end, there is a need to overcome a major obstacle, a 
set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry 
or the DNA binding of the transcription factor. Two major signaling steps are 
required for the elimination of the inhibitors: activation of the IκB kinase 
(IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB 
degradation involve different ubiquitination modes; the latter is mediated by a 
specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3, 
β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and 
thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB 
ubiquitination and degradation is a very efficient process, often resulting in 
complete degradation of the key inhibitor IκBα within a few minutes of cell 
stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs 
and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have 
been worked out, the development of β-TrCP inhibitors might be a feasible 
therapeutic approach for NF-κB-associated human disease. However, we may still 
need to advance our understanding of the mechanism of IκB degradation as well as 
of the diverse functions of β-TrCP in vivo.