NF-kB signaling pathway
The Nuclear factor kappa B (NF-kB) plays a crucial role
in immune and inflammatory responses through the regulation of genes encoding
pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and inducible
enzymes. Transcription factors of the NF-kB family are
activated in response to signals that lead to cell growth, differentiation, apoptosis and
other events. NF-kB is activated by signals that activate
Nuclear factor NF-kappa-B inhibitor kinase (IKK) resulting
in the phosphorylation of Nuclear factor of kappa light polypeptide gene enhancer in
B-cells inhibitor (I-kB), this targets
I-kB for degradation in the proteasome and frees the
NF-kB dimer, which then translocates to the nucleus and
activates target genes .
Tumor necrosis factor (TNF-alpha) binds to one of two
distinct receptors, Tumor necrosis factor receptor superfamily, member 1A and 1B
(TNF-R1 and TNF-R2), and
triggers activation of the canonical NF-kB signaling
pathway. Upon ligand binding TNF-R1 recruits
TNFRSF1A-associated via death domain (TRADD) which then
activates TNF receptor-associated factor 2 (TRAF2), whereas
TNF-R2 directly interacts with
TRAF2. Subsequent (TRAF2)/
Mitogen-activated protein kinase kinase kinase 14
IKK/ I-kB signaling cascade
leads to NF-kB activation , .
The non-canonical pathway of NF-kB activation is utilized
in response to the ligation of only certain TNF receptor
superfamily members, for example Lymphotoxin beta receptor
(LTBR(TNFRSF3)). In the non-canonical pathway,
TRAF stimulates NIK, which
subsequently activates IKK-alpha by phosphorylation.
IKK-alpha promotes the processing of nuclear factor of kappa
light polypeptide gene enhancer in B-cells 2 (NF-kB2 (p100))
from p100 to p52 form. Further processed NF-kB2 is bound to
V-rel reticuloendotheliosis viral oncogene homolog B (RelB).
NF-kB p52/RelB dimer is translocated into the nucleus to
affect gene transcription. The non-canonical pathway is independent on
IKK-beta and IKK-gamma , .
T cell receptor (TCR) and CD28 molecule
(CD28) can stimulate NF-KB via
Protein kinase C theta (PKC-theta)-dependent pathway , , . Also CD28
triggers V-akt murine thymoma viral oncogene homolog 1
(AKT)-mediated pathway .
Upon binding of Interleukin 1 (IL-1), the Interleukin 1
receptor type I (IL-1RI) associates with Interleukin 1
receptor accessory protein (IL1RAP), forming a functional
signaling receptor complex that recruits myeloid differentiation primary response gene 88
(MyD88). This leads to the translocation into this complex
of Interleukin-1 receptor-associated kinase (IRAK1/2)
together with Toll interacting protein (TOLLIP).
IRAK1 binds TNF receptor-associated factor 6
(TRAF6). After dissociation from the receptor complex,
NIK or Mitogen-activated protein kinase kinase kinase 1
(MEKK1(MAP3K1))-dependent phosphorylation of
Lipopolysacccharide (LPS) in
complex with Lipopolysaccharide binding protein (LBP) binds
CD14 molecule (CD14) on the cell membrane. It transfers
LPS to lymphocyte antigen 96
(MD-2) and Toll-like receptor 4
(TLR4). TLR4 via binding
MyD88  and/or possibly Receptor-interacting
serine-threonine kinase 2 (RIPK2) induces
NF-kB-activating cascade .
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