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NF-kappaB Signaling

NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) represent a group of homo- or heterodimeric transcription factors that are central in a network of various signal transduction pathways. A vast array of signals such as cytokines, growth factors and hormones, infections, oxidative stress, certain drugs, and chemical substances are transmitted to the NF-kB complexes and passed on to influence processes ranging from cell survival, apoptosis, and proliferation to immune response and inflammation. In addition, there is considerable crosstalk with other signaling pathways such as MAPK signaling and the p53 pathway. They are therefore highly pleiotropic, i.e. they influence a multitude of phenotypic traits2.

NF-kB is a homo- or heterodimeric complex formed in mammals by the Rel homology domain (RHD)-containing proteins RelA/p65, RelB, c-Rel, NFKB1/p105/p50, and NFKB2/p100/p52. The heterodimeric RELA/p50 complex of the canonical pathway appears to be the most abundant one. All NF-kB proteins have an N-terminal RHD which plays an essential role in DNA binding, as dimerization interface and for the binding to IkB inhibitors. NF-kB proteins do however differ in their C-terminal: class I proteins RELA, RELB and c-Rel contain are characterized by a trans-activator domain whereas class II proteins NFKB1/p105/p50 and NFKB2/p100/p52 have ankyrin repeat transrepression domain3.

In the canonical pathway, NF-kappaB are kept in an inactive state in the cytoplasm through interaction with inhibitory IkB proteins. Upon stimulation of the NF-kB signaling by one of the abovementioned stimuli these regulators are phosphorylated by an IKK kinase complex4 composed of protein kinases IKK-alpha, IKK-beta, and NEMO. The phosphorylation marks the IkB inhibitors for proteasomal degradation, thus setting NF-kB free. Once freed, NF-kB are further activated by post-translational modification and translocated to the nucleus where it interacts with specific kB elements5. Depending on the cell type and nature of the received stimulus the non-canonical pathway6 can be engaged. The core regulator for this pathway is NF-kB inducing kinase (NIK) which activates IKK-alpha, thus leading to phosphorylation of p100. p100 is then processed to p52 leading to the activation and nuclear translocation of the p52/RelB NF-kB dimer.

The canonical pathway does not depend on protein synthesis and responds rapidly to numerous stimuli for a wide variety of downstream effects. In contrast, the non-canonical pathway is slow and persistent and responds only to a subset of signals for more specific effects.

References

  • Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013 Aug 2;12:86. doi: 10.1186/1476-4598-12-86. PMID: 23915189; PMCID: PMC3750319.
  • Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011 Jul 19;12(8):695-708. doi: 10.1038/ni.2065. PMID: 21772278.
  • Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000034. doi: 10.1101/cshperspect.a000034. PMID: 20066092; PMCID: PMC2773619.
  • Israël A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a000158. doi: 10.1101/cshperspect.a000158. PMID: 20300203; PMCID: PMC2829958.
  • King CC, Sastri M, Chang P, Pennypacker J, Taylor SS. The rate of NF-κB nuclear translocation is regulated by PKA and A kinase interacting protein 1. PLoS One. 2011 Apr 27;6(4):e18713. doi: 10.1371/journal.pone.0018713. PMID: 21556136; PMCID: PMC3083391.
  • Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011 Jan;21(1):71-85. doi: 10.1038/cr.2010.177. Epub 2010 Dec 21. PMID: 21173796; PMCID: PMC3193406.

Adaptors

Cytokines

Enzymes

Growth factors

Inhibitors

NFKBIA (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, alpha):

NFKBIB (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, beta):

NFKBIE (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, epsilon):

NFKBIZ (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, zeta):

Kinases

Protein kinases

IKBKG (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase gamma):

IKBKB (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase beta):

MAP3K14 (Mitogen-Activated Protein Kinase Kinase Kinase 14):

Receptors

LTBR (Lymphotoxin beta Receptor (TNFR Superfamily, Member 3)):

TNFRSF11A (Tumor Necrosis Factor Receptor Superfamily, Member 11a, NFKB Activator):

Transcription factors

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