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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 89

cellular processes. A question therefore arises as to how There are two remarkable aspects of the NF-κBsig-
the fidelity of these signalling pathways is achieved in or- nalling pathway. Firstly, it can control a very large number
der to reduce cross-talk and to ensure that they carry out of genes that are often activated as large cohorts in spe-
their particular functions. It seems that much of this fi- cific cells by different stimuli. Secondly, it is used by a
delity is achieved by using molecular scaffolds to hold number of different signalling systems with subtle vari-
together all the components of each signalling pathway in ations in the mechanism and the components that are used
a multimolecular complex. In this way, information can to convey information into the nucleus. The tumour nec-
be passed from one component to the next without inter- rosis factor α (TNFα) signalling pathway and the Toll
ference from other signalling pathways (Module 6: Figure receptor signalling pathway will be described to illustrate
signalling hierarchies). Examples of such scaffolds are the the main features of the NF-κB signalling pathway. The
scaffolding proteins kinase suppressor of Ras 1 (KSR1) receptor activator of nuclear factor κB(NF-κB) ligand
(Module 2: Figure ERK signalling) and JNK-interacting (RANKL), which is a transmembrane protein that belongs
protein 1 (JIP1) (Module 2: Figure JNK signalling). to the TNF family of cytokines, activates the RANKL re-
Other determinants of fidelity are the docking sites ceptor (RANK) that uses the NF-κB signalling pathway
that enable the different mitogen-activated protein kinases to control osteoclastogenesis (Module 8: Figure osteoclast
(MAPKs) to bind to their specific downstream effectors. differentiation).

Nuclear factor κB(NF-κB) signalling toolkit
Phenotypic remodelling of the mitogen-activated The NF-κB signalling toolkit is composed of four main
protein kinase (MAPK) signalling pathway classes of signalling components (Module 2: Table NF-κB
The mitogen-activated protein kinase (MAPK) signalling signalling toolkit).
pathway operates autoregulatory loops in that the dif-
ferent signalling pathways can regulate the expression Nuclear factor κB(NF-κB)/Rel family
of their own signalling components. For example, the The nuclear factor κB(NF-κB)/Rel family consists of
extracellular-signal-regulated kinase (ERK) pathway can five members (Module 2: Table NF-κB signalling toolkit).
regulate the expression of MAPK phosphatase 1 (MKP1) There is some confusion concerning the nomenclature of
(Module 2: Figure ERK signalling), whereas the c-Jun N- this family. The notations shown at the beginning of the
terminal kinase (JNK) pathway induces the expression of table (p50, p52, p65, RelB and c-Rel) will be used here.
JNK-interacting protein 1 (JIP1) (Module 2: Figure JNK All members of the family share an N-terminal Rel ho-
signalling). This induction of MKP1 and JIP1 effectively mology domain (RHD), which binds to DNA (Module
set up negative-feedback loops that limit the activity of the 2: Figure NF-κB, IκB and IKK structure). The RHD is
MAPK signalling pathway, and is an example ofsignalsome also used to associate NF-κBwiththe inhibitor of nuclear
stability. factor κB(NF-κB) (IκB) proteins. The NF-κB/Rel family
Phenotypic remodelling of the MAPK signalsome may of transcription factors normally function as heterodimers,
result in the abnormal cell proliferation observed in and the p50/p65 complex was the first to be discovered.
polycystic kidney disease (Module 12: Figure polycystins Some of the family members can form homodimers, such
and polycystic kidney disease). as p50/p50 and p52/p52, and these act as repressors of
NF-κB-sensitive genes.

Nuclear factor κB(NF-κB) signalling Inhibitor of nuclear factor κB(NF-κB) (IκB)
pathway The inhibitor of nuclear factor κB(NF-κB) (IκB) family
The transcription factor nuclear factor κB(NF-κB) is are characterized by an ankyrin repeat domain (Module
activated by a large number of external stimuli such as 2: Figure NF-κB, IκB and IKK structure), which func-
the tumour necrosis factors (TNFs), interleukin-1 (IL-1) tions in its interaction with NF-κB to form the inactive
and the pathogen-associated molecular patterns (PAMPs), complex that resides in the cytoplasm. The IκB inhibits
which are responsible for controlling processes such as transcription by masking the nuclear localization signal
inflammation, cell proliferation and apoptosis. NF-κBbe- (NLS) on NF-κB, which thus prevent it from entering the
longs to the group of transcription factors that lie latent in nucleus. The NF-κB/IκB complex remains inactive within
the cytoplasm and then translocate into the nucleus upon the cytoplasm until the IκB is removed following activa-
activation (mechanism 2 in Module 4: Figure transcription tion of the nuclear factor κB(NF-κB) signalling pathway.
factor activation). This diversity of downstream effector Much of the specificity within the NF-κB signalling path-
processes indicates that there must be separate signalling way depends on these IκB isoforms being able to bind to
pathways, and this is evident from the nuclear factor κB different dimers of the NF-κB/Rel family.
(NF-κB) signalling toolkit, which contains multiple iso-
forms both of the transcription factors (the NF-κB/Rel Inhibitor of nuclear factor κB(IκB) kinases (IKKs)
family) and of the activation components. This complex- The inhibitor of nuclear factor κB(IκB) kinases (IKKs)
ity is carried through to the nuclear factor κB(NF-κB) function as heterodimers and are responsible for phos-
signalling pathway, where there are many variations on phorylating IκB to mark it for subsequent degradation
the basic theme of NF-κB activation (i.e. Mechanism 2 in by the proteasome. The kinase domain is located in the
Module 4: Figure transcription factor activation). N-terminus, whereas the C-terminus has leucine zipper

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