Biomedical Engineering Reference
In-Depth Information
p105
Alternative
, CD40,
BAFF, RANKL
LT
αβ
TNFα
IL-1, LPS
NIK
NEMO
IKK
α
IKKβ
IKK
α
IKK
α
p105
p50
p50
RelB
p100
TPL-2
TPL-2
Proteasome
-mediated
proteolysis
MEK
p50
p50
p52
RelB
ERK
Cytoplasm
Nucleus
p50
p50
RelB
p52
FIGURE 4.6
Model of signaling pathways regulating NF-κB1 p105 and NF-κB2 p100. The
p105 pathway is involved in regulating immune and inflammatory responses. In this pathway,
agonist stimulation induces the classical IKK complex to phosphorylate the p105 PEST region,
triggering p105 polyubiquitination and subsequent proteolysis by the proteasome. This
releases p50 homodimers to translocate into the nucleus and positively or negatively regulate
gene expression. Signal-induced p105 proteolysis also releases TPL-2, resulting in its acti-
vation. p105-free tumor progression locus-2 (TPL-2) phosphorylates and activates MAP/ERK
kinase (MEK), which in turn phosphorylates and activates ERK. The alternative NF-κB
pathway that regulates the proteolysis of p100 is triggered by a subset of receptors that activate
NF-κB. Receptor activation induces NF-κB inducing kinase (NIK) activity, in part by upreg-
ulating its expression, which phosphorylates and activates IKKα. IKKα directly phosphory-
lates p100, inducing its polyubiquitination and processing by the proteasome. This produces
p52, which translocates into the nucleus in a complex with RelB to regulate the expression
of genes important in controlling the organization of secondary lymphoid organs and humoral
immune responses.
