Biomedical Engineering Reference
In-Depth Information
the most potent IKK-K is IKK itself (D. Rothwarf, M. Delhase, and M. Karin, unpub-
lished observation). As such, phosphorylation of the activation loop during kinase
activation does not necessarily mean that this was the original activating event. (ii)
Multimerization of IKK, thereby inducing autophosphorylation and kinase activation
by close proximity of catalytically active IKK
dimers. In this model, multimeriza-
tion of IKK might be driven by other upstream molecules binding to one of the IKK
components, for example, NEMO. However, as discussed above, the IKK complex is
already multimeric and therefore the activating event may induce a conformational
change that brings the catalytic subunits closer to each other. (iii) Direct modification
of one of the IKK components other than phosphorylation, e.g., ubiquitination. Such
a modification of NEMO has been reported, at least for some pathways leading to
NF-
α/β
B activation [40,41]. This modification may alter the conformation of the complex
leading to its autoactivation. As mentioned above, based on experiments with zinc
finger mutants of NEMO [24,25], it is probable that different mechanisms of IKK
activation exist, which are engaged by different NF-
κ
B activating stimuli. Therefore,
the different mechanisms proposed to explain IKK activation will be discussed in the
context of the major signal transduction pathways that lead to NF-
κ
κ
B activation.
3.4.1
A
CTIVATION
OF
THE
NF-
B P
ATHWAY
BY
M
EMBERS
OF
THE
TNF R
ECEPTOR
(TNFR) F
AMILY
κ
As mentioned earlier, based on the different IKK substrates involved during NF-
κ
B
activation, a classic and an alternative NF-
κ
B pathway can be discerned. Based on
genetic evidence, IKK
β
is usually essential for activation of the classic NF-
κ
B
pathway (although in some cases IKK
α
is required), while IKK
α
is critical for
activation of the alternative NF-
B pathway. As NEMO is not required for the
alternative pathway, indicating differences in the molecular mechanisms of activa-
tion, we will discuss regulation of the two pathways separately.
κ
3.4.1.1
Activation of the Classic NF-
κ
B Pathway by TNFR
Family Members
The pathway that leads to NF-
B from members of the TNFR family is one of the
best-characterized and first studied NF-
κ
B signaling pathways. Among different
TNFR family members, most of our knowledge relies on data obtained from the
major TNF
κ
receptor TNF-RI, the study of which led to the biochemical identifi-
cation of the IKK complex [11]. We will therefore focus this discussion primarily
on TNFRI signaling. A hallmark of the receptors of the TNFR family is that they
do not contain enzymatic activity, but depend on recruitment of intracellular adaptors
and signaling molecules to initiate signal transduction. Several important intracel-
lular molecules have been identified, including members of the TRAF (TNFR asso-
ciated factor) family, that are critically involved in NF-
α
B activation [42]. Based on
their eponymous C-terminal TRAF-domain, six members of this family have been
identified. With the exception of TRAF1, all TRAFs contain N-terminal Zinc-binding
motifs including a RING finger, which might be considered as TRAF effector
domains, and all contain a C-terminal TRAF domain that can further be divided in
κ
