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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.


1www.ncbi.nlm.nih.gov/pubmed/23915189

2www.ncbi.nlm.nih.gov/pubmed/21772278

3www.ncbi.nlm.nih.gov/pubmed/20066092

4www.ncbi.nlm.nih.gov/pubmed/20300203

5www.ncbi.nlm.nih.gov/pubmed/21556136

6www.ncbi.nlm.nih.gov/pubmed/21173796

Adaptors

MYD88 (Myeloid Differentiation Primary Response Gene (88)):

This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal...   More...

TRADD (TNFRSF1A-Associated Via Death Domain):

The protein encoded by this gene is a death domain containing adaptor molecule that interacts with TNFRSF1A/TNFR1 and mediates programmed cell death signaling and NF-kappaB activation. This protein binds adaptor protein TRAF2, reduces the recruitment of inhibitor-of-apoptosis proteins (IAPs) by TRAF2, and thus suppresses TRAF2 mediated apoptosis. This protein can also interact with receptor...   More...

KHDRBS1 (KH Domain Containing, RNA Binding, Signal Transduction Associated 1):

SLC39A3 (Solute Carrier Family 39 (Zinc Transporter), Member 3):

Cytokines

IL1A (Interleukin 1 alpha):

The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is a pleiotropic cytokine involved in various immune responses, inflammatory processes, and hematopoiesis. This cytokine is produced by monocytes and macrophages as a proprotein, which is proteolytically processed and released in response to cell injury, and thus induces apoptosis. This gene and...   More...

TNF - Tumor Necrosis Factor

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation,...   More...

Enzymes

TRAF1 (TNF Receptor-Associated Factor 1):

The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from various receptors of the TNFR superfamily. This protein and TRAF2 form a heterodimeric complex, which is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this...   More...

TRAF2 (TNF Receptor-Associated Factor 2):

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms a heterodimeric complex with TRAF1. This protein is required for TNF-alpha-mediated activation of MAPK8/JNK and...   More...

Growth factors

EGF (Epidermal Growth Factor):

This gene encodes a member of the epidermal growth factor superfamily. The encoded protein is synthesized as a large precursor molecule that is proteolytically cleaved to generate the 53-amino acid epidermal growth factor peptide. This protein acts a potent mitogenic factor that plays an important role in the growth, proliferation and differentiation of numerous cell types. This protein acts by...   More...

NGFB (Nerve Growth Factor beta):

This gene is a member of the NGF-beta family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic...   More...

Inhibitors

BCL3 (B-Cell CLL/lymphoma 3):

This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional co-activator that activates through its association with NF-kappa B...   More...

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

This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have...   More...

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

IRAK1 (Interleukin-1 Receptor-Associated Kinase 1):

This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene....   More...

RIPK1 (Receptor (TNFRSF)-Interacting serine-threonine Kinase 1):

Serine-threonine kinase which transduces inflammatory and cell-death signals (necroptosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication...   More...

Protein kinases

CHUK (conserved Helix-Loop-Helix Ubiquitous Kinase):

This gene encodes a member of the serine/threonine protein kinase family. The encoded protein, a component of a cytokine-activated protein complex that is an inhibitor of the essential transcription factor NF-kappa-B complex, phosphorylates sites that trigger the degradation of the inhibitor via the ubiquination pathway, thereby activating the transcription factor. [provided by RefSeq, Jul 2008].   More...

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

This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. Multiple transcript variants encoding...   More...

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

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

Receptors

EGFR (Epidermal Growth Factor Receptor):

The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation....   More...

IL1R1 (Interleukin 1 Receptor, Type I):

The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This protein is a receptor for interleukin alpha (IL1A), interleukin beta (IL1B), and interleukin 1 receptor, type I(IL1R1/IL1RA). It is an important mediator involved in many cytokine induced immune and inflammatory responses. This gene along with interleukin 1 receptor, type II (IL1R2),...   More...

TNFRSF1A (Tumor Necrosis Factor Receptor Superfamily, Member 1A):

The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is one of the major receptors for the tumor necrosis factor-alpha. This receptor can activate NF-kappaB, mediate apoptosis, and function as a regulator of inflammation. Antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRADD and TRAF2 have been shown to interact with this...   More...

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

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

Transcription factors

NFKB1 (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells 1):

This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as...   More...

RELB - V-Rel Reticuloendotheliosis Viral Oncogene Homolog B

NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF- kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers...   More...
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