α and interleukin-1 (IL-1). The C-terminus of IKKγ subunit serves as a docking site
for upstream signals, and the N-terminal half of IKKγ (minus the first 100 amino
acids) binds to IKKβ. This results in phosphorylation of specific conserved serine
residues (S177 and S181) within the T-loop (activation domain) in the cat alytic
domain of IKKβ. Activation of the canonical NF-κB pathway involving degradation
of IκB is mostly dependent on the IKKβ subunit, and is essential for innate immunity
(Li et al., 1999a; Delhase et al., 1999; Li et al., 1999b; Senftleben et al., 2001b). A
second pathway is involved in activation of the NF-κB dimer between RelB and p52
(Solan et al., 2002). RelB is held in an inactive cytoplasmic complex by NF-κB2p100
until IKKα-dependent degradation of the IκB-like COOH-terminus of p100 allows
the release and nuclear translocation of the active RelB/p52 dimer (Solan et al., 2002).
The activation of the RelB/p52 dimer by proteolytic processing is important for
lymphoid organ development and the adaptive immune response (Senftleben et al.,
2001a).
In addition to the release and nuclear translocation of the dimer, transcriptional
induction of target genes by NF-κB requires phosphorylation of Rel proteins by
serine/threonine kinases, such as casein kinase II and Akt (Zhong et al., 1997;
Sizemore et al., 1999; Madrid et al., 2000; Wang, D. et al., 2000).
Role of NF-κB in protection of cells from death receptor-induced
apoptosisTargeted disruption of the RelA subunit of NF-κB or either IKKβ or IKKγ/NEMO
results in embryonic death of mice as a result of massive hepatic (liver) apoptosis (Beg
et al., 1995; Li et al., 1999a; Rudolph et al., 2000). RelA-/- fibroblasts, unlike their
wild-type (RelA+/+) counterparts, exhibit a profound sensitivity to TNF-α-induced
apoptosis (Beg and Baltimore, 1996). Likewise, IKKβ-/- fibroblasts, or cells stably
transfected with phosphorylation mutants of iκBα, fail to activate NF-κB and display
increased sensitivity to TNF-α-induced death (Van Antwerp et al., 1996; Li et al.,
1999b; Senftleben et al., 2001b). These observations demonstrate an important role
of NF-κB in protecting cells from death receptor-induced apoptosis.
Engagement of TNFR1 by TNF leads to the recruitment of the adapter protein
TRADD to the clustered DDs of the trimerized receptors. TRADD, in turn, serves
as a platform for the docking of multiple signaling molecules to the activated receptor
complex. As discussed earlier, TNF-induced apoptosis is triggered by recruit-ment
of the adapter molecule FADD to the TNFR1-TRADD complex. Therefore, the
apoptotic signaling pathways triggered by different members of the death receptor
family (TNFR1, CD95/Fas, and TRAIL-Rl/R-2) are all initiated by ligand-induced
recruitment of FADD and FADD-mediated activation of caspase-8. While they share
a common death-signaling pathway, these receptors exhibit a differential ability to
activate NF-κB. While FasL is unable to activate NF-κB, TNF-α induces activation
of the transcription factors, NF-κB and JNK/AP1, via recruitment of receptor-
interacting protein (RIP) and TNFR-associated factor-2 (TRAF-2) to the receptor
complex. TRAF-2 and RIP activate the NF-κB-inducing kinase (NIK), which, in
DEATH RECEPTORS IN APOPTOSIS 15