Regulation of IKK - Transcription Factors NF-kappaB - page 34

(a) (b)

BAFF

TNF α

BAFFR

TNFR I

TRAF3

TRADD

Ub NIK

TRAF2

Ub

AF3

TR

NEMO

MEKK3

TAB2/3

IKK α IKK

β

NIK NIK

IKK α

P P

SCF β-TrCP

p100 RelB

p50 p65

Ub Ub

Ub Ub

P

SCF β-TrCP

p50 p65 RelB p52

FIGURE 3.2 Schematic representation of the TNF α -induced classic and BAFF-induced alter-

native NF- leads to recruitment of various adaptor

molecules, including TRADD, TRAF2 (and TRAF5), and RIP1. (a) TRAF2 controls recruit-
ment of the IKK complex through interaction with its catalytic subunits. TRAF2 is also
required for ubiquitination of RIP1 and possibly TRAF2 itself. RIP1 binds to NEMO and
supports complex formation, possibly also changing the conformation of the IKK complex.
Whether RIP1 action depends on ubiquitination is not clear. TAB2 and TAB3 interact with
TRAF2 and TAK1, possibly inducing oligomerization and activation of TAK1. This interaction
also brings TAK1 near the other components of the signaling complex, including IKK

κ B pathways. TNFRI engagement by TNF α

, which
may be directly phosphorylated by TAK1. How MEKK3 is brought into proximity of the
signaling complex is less clear, but may involve interaction with RIP1, rather than TAB2/3
and TRAF2/5. Active IKK phosphorylates I

β

Bs on conserved serines leading to its recognition
by the E3 ubiquitin ligase SCF βTrCP , polyubiquitination and degradation by the 26S proteasome.
Liberated NF-

κ

B dimers are transported to the nucleus where they drive gene transcription.
In nonactivated cells, the kinase NIK is constitutively bound to TRAF3, which controls NIK
stability and expression levels. (b) Receptor stimulation leads to recruitment of TRAF3, which
is followed by its degradation by an uncharacterized mechanism. Degradation of TRAF3
results in increased stability and expression levels of NIK, possibly also initiating kinase
activation by autophosphorylation. NIK itself binds to p100 and supports recruitment of I

κ

ΚΚα .

NIK directly phosphorylates IKK α at serines in its activation loop, resulting in kinase acti-

vation, followed by IKK -dependent phosphorylation of p100. Phosphorylated p100 is rec-

ognized by the E3 ubiquitin ligase SCF

α

TrCP , resulting in polyubiquitination and partial
proteolytic degradation by the 26S proteasome. Free p52:RelB dimers translocate to the
nucleus and drive gene transcription.

β