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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 91

Module 2: Figure NF-κB, IκB and IKK structure

NF- B/Rel familyκ
p65 RHD

c-Rel RHD
RelB RHD
p50 RHD

p52 RHD
Ankyrin repeat
I B familyκ domain

IBκα
IBκβ
IBκγ

IBκε

Bcl3

IKK family
IKKα Ser kinase ZIP HLH

IKKβ Ser kinase ZIP HLH

NEMO CCD CCD ZIP
Zn finger

The structure of components of the nuclear factor κB(NF-κB) signalling toolkit.
The nuclear factor κB(NF-κB)/Rel family all share a Rel homology region (RHD). The mauve box in the N-terminal region of RelB is a putative leucine
zipper region. The p50 and p52 isoforms also have ankyrin repeat domains that resemble those found in the inhibitor of NF-κB(IκB) family. The IκB
kinase (IKK) family has both kinase (IKKα and IKKβ) and regulatory components [NF-κB essential modulator (NEMO)]. ZIP, leucine zipper; HLH,
helix--loop--helix domain; CCD, coiled-coil domain. Redrawn from Handbook of Cell Signalling, Vol. 3 (R.A. Bradshaw and E.A. Dennis, eds), Westwick,
J.K., Schwamborn, K. and Mercurio, F., NFκB: a key integrator of cell signalling, pp. 107--114. Copyright (2003), with permission from Elsevier; see
Westwick et al. 2003.

Tumour necrosis factor (TNF)-receptor-associated and stimuli derived from pathogens that are known
factor (TRAF) family as pathogen-associated molecular patterns (PAMPs)
The tumour necrosis factor (TNF)-receptor-associated (Module 11: Figure formation and action of PAMPs).
factor (TRAF) family has seven members, which func- These PAMPs act on Toll-like receptors (TLRs) and the
tion in the signalling pathways of various TNF receptor IL-1 receptor (IL-1R) and these form a TLR/IL-1R family
superfamily and Toll/interleukin-1 receptor mechanisms. that act through a similar Toll receptor signalling path-
TRAF2 functions as an adaptor for the tumour necrosis way (Module 1: Figure cytokines). The primary func-
factor receptor (Module 2: Figure NF-κB activation). In tion of this signalling pathway is to stimulate the tran-
the case of osteoclasts, it is TRAF6 that couples the scriptional processes that result in the expression of a
receptor activator of nuclear factor κB(NF-κB) ligand wide range of inflammatory cytokines and immunoreg-
(RANKL) receptor (RANK) to downstream signalling ulators (Module 2: Figure Toll receptor signalling). As
pathways (Module 8: Figure osteoclast differentiation). such, the Toll receptor signalling pathway has to trans-
mit information from the TLRs and the IL-1R on the
cell surface to the transcriptional factors such as nuclear
Toll receptor signalling pathway factor κB(NF-κB) and activating protein 1 (AP-1) (c-
The Toll receptor signalling pathway plays a central Jun/Fos) that act within the nucleus. This information
role in inflammatory responses (Module 11: Figure in- transfer system will be illustrated by reference to the
flammation). This pathway is activated by two types of response of the receptor TLR4 to lipopolysaccharide (LPS)
stimuli: cytokines, represented by interleukin-1 (IL-1), (Module 11: Figure formation and action of PAMPs). As

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