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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 90

Module 2: Table NF-κB signalling toolkit ‘classical’ mechanisms as illustrated by the following se-
The nuclear factor κB(NF-κB) signalling toolkit quence of events (Module 2: Figure NF-κB activation):
Nuclear factor κB (NF-κB)
transcription system Comments
NF-κB/Rel family of 1. Occupation of the TNF receptor (TNF-R) by TNF
transcription factors induces receptor oligomerization to form a complex
p50 (NF-κB1) p50 has a p105 precursor protein that attracts the adaptors TRADD and the TNFR-
p52 (NF-κB2) p52 has a p100 precursor protein
p65 (NF-κB3, also known as associated factor 2 (TRAF2), which is an adaptor that
RelA) belongs to the TNF-receptor-associated factor (TRAF)
RelB family.
c-Rel
Inhibitor of NF-κB(IκB) family 2. TRAF2 is a RING domain E3 ubiquitin ligase that as-
IκBα Bind to p65 and c-Rel sociates with the heterotrimeric ubiquitin-conjugating
IκBβ (E2) complex that contains Ubc13 and Uev1A. This
IκBγ
IκBε is a K63 ubiquitinating complex that adds ubiquitin
IκBζ Binds preferentially to p50 chains to TRAF2 and this then helps to recruit the
Bcl3 B cell lymphoma 3 binds to receptor-interacting protein 1 (RIP1), which is also
p50/p50 and p53/p53
homodimers. ubiquitinated. These ubiquitin chains provide an im-
Inhibitor of NF-κB(IκB) portant scaffolding role in the assembly of additional
kinases (IKKs) elements of the signal transduction pathway. For ex-
IKKα
IKKβ ample TRAF2 interacts with apoptosis signal-regulat-
NEMO (IKKγ) A regulatory subunit responsible ing kinase 1 (ASK1) that then relays information to
for the interaction with both the JNK signalling and p38 signalling pathways
upstream kinases on the
receptor complex (Module 2: 3. The developing receptor complex attracts additional
Figure NF-κB activation) components such as the transforming growth factor
Associated proteins β activated kinase-1 (TAK1), the TAK1-binding (TAB)
Cdc37
Hsp90 proteins 1 to 3 (TAB1-3) and the multisubunit cytoplas-
mic complex containing the inhibitor of NF-κB(IκB)
kinase (IKK) α/IKKβ dimer and the regulatory NF-κB
essential modifier (NEMO) subunit, which is a central
and helix--loop--helix domains (Module 2: Figure NF-κB,
player in this translocation sequence.
IκB and IKK structure). These two protein-association
4. Once this complex is complete, the TAK1 phos-
domains enable the enzyme to associate with a large multi-
phorylates and activates IKKβ.
subunit complex in the cytoplasm. Another important 5. The IKKβ then phosphorylates IκBα on two sites (Ser-
component of this complex is nuclear factor κB(NF- 32 and Ser-36).
κB) essential modulator (NEMO) (IKKγ), which is a 6. The phosphorylated IκBα is then susceptible to ubi-
regulatory/structural subunit responsible for the inter- quitination by the Skp1/cullin/F-box (SCF) ubiquitin
action with upstream kinases on the receptor as part of ligase.
the tumour necrosis factor α (TNFα) signalling pathway 7. The polyubiquitinated IκBα is then sent to the protea-
(Module 2: Figure NF-κB activation). In the case of NF-κB some, where it is degraded, resulting in the liberation
activation in T-cells, the IKK is stimulated by protein of the NF-κB heterodimer p50/p65.
kinase θ (PKCθ) using the scaffolding proteins CARMA1,
8. The NF-κB is imported into the nucleus, where it
Bcl10 and MALT1 (Module 9: Figure TCR signalling).
The tumour suppressor CYLD binds to NEMO and binds to the κB promoter elements to activate ex-
inhibits the subsequent phosphorylation of IκBaspartof pression of many different genes (Module 4: Figure
the TNFα signalling pathway. NF-κB activation and function). One of these genes
is hypoxia-inducible factor 1α (HIF-1α), which thus
serves to link the innate immune response to the hyp-
Tumour necrosis factor α (TNFα) oxic response.
signalling pathway 9. Transcription ceases when NF-κB is exported from the
The basic operation of the nuclear factor κB(NF-κB)/Rel nucleus. One of the genes activated by NF-κBisIκBα,
family of transcription factors is that they are activated which thus sets up a negative-feedback loop, because it
in the cytoplasm and then translocate into the nucleus to binds to the NF-κB that is exported from the nucleus
activate transcription (mechanism 2 in Module 4: Figure to reconstitute the inactive cytoplasmic complex.
transcription factor activation). There are a number of vari- 10. The ubiquitin signalling pathway contributes to the re-
ations in the way that this translocation process is initiated, covery of this signalling cascade after TNFα is with-
depending on the nature of the incoming signals and the drawn by removing the ubiquitin scaffolds that hold to-
receptors that are being activated. In addition to the activ- gether the transducing complex. The deubiquitinating
ation of NF-κB, these non-enzyme-containing receptors enzymes A20 and CYLD are particularly active in re-
can activate other signalling pathways (Module 1: Figure moving the ubiquitin chains. The reversible ubiquit-
cytokines). In this section, attention will focus on the NF- ination of signal transducing components is thus an
κB signalling pathway, which is used by the tumour nec- essential part of the processing of information by this
rosis factor α (TNFα). It is considered to be one of the TNF signalling pathway.

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