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Signalisation NF-kappaB

Les NF-kappaB (facteurs nucléaires améliorateurs de chaîne légère kappa de cellules B activées) sont un groupe de facteurs de transcription homo- ou hétérodimétriques qui jouent un rôle capital dans un réseau de nombreuses voies de transduction de signaux. Un large éventail de signaux tels que les cytokines, les facteurs et hormones de croissance, les infections, le stress oxydatif, certaines drogues, et les substances chimiques, sont transmis aux complexes NF-kB et agissent sur des processus tels que la survie des cellules, l’apoptose, et la prolifération, mais aussi la réponse immunitaire et l’inflammation. En outre, il existe de nombreuses interactions avec d’autres voies de signalisation telles que la signalisation MAPK et la voie p531 . Ils sont donc hautement pléiotropiques, c’est-à-dire qu’ils influencent une multitude de caractères phénotypiques2.

Les NF-kappaB constituent un complexe homo- ou hétérodimérique présent chez les mammifères dans les protéines où l’on trouve le domaine d’homologie RHD : RelA/p65, RelB, c-Rel, NFKB1/p105/p50, et NFKB2/p100/p52. Le complexe hétérodimérique RELA/p50 de la voie canonique apparaît être le plus abondant. Toutes les protéines NF-kappaB ont un RHD N-terminal qui joue un rôle capital dans la liaison de l’ADN, en tant qu’interface de dimérisation et pour la liaison avec les inhibiteurs d’IkappaB. Les protéines NF-kappaB diffèrent toutefois dans leur C-terminal : les protéines de classe I appelées RELA, RELB et c-Rel sont caractérisées par un domaine transactivateur alors que celles de classe II appelées NFKB1/p105/p50 et NFKB2/p100/p52 ont un domaine de transrepression à répétition ankyrine3.

Avec la voie canonique, les NF-kappaB sont maintenus dans un état inactif dans le cytoplasme grâce à l’interaction avec les protéines inhibitrices IkappaB. Après une stimulation de la signalisation NF-kappaB effectuée par l’un des stimuli susmentionnés, ces régulateurs sont phosphorylé par un complexe kinase IKK4 constitué des protéines kinases IKKalpha, IKKbeta et NEMO. La phosphorylation marque les inhibiteurs d’IkappaB en vue d’une dégradation protéasomale, libérant ainsi les NF-kappaB. Une fois libérés, les NF-kB sont alors activés par une modification post-translationnelle et transloqués vers le noyau où ils interagissent avec des éléments kappaB spécifiques5. En fonction du type de cellule concernée et de la nature du stimulus reçu, c’est la voie non canonique6 qui peut entrer en jeu. Le régulateur central de cette voie est le NF-kappaB induisant la kinase (NIK) qui active l’IKKalpha, entraînant ainsi la phosphorylation du p100. Le p100 se transforme alors en p52, ce qui conduit à l’activation et à la translocation nucléaire du dimère NF-kappaB p52/RelB et induit l’expression des gènes ciblés.

La voie canonique ne dépend pas de la synthèse des protéines et répond rapidement à de nombreux stimuli dans une multitude d’effets synergétiques. En revanche, la voie non canonique est lente et persistante, et elle ne répond qu’à un sous-ensemble de signaux, avec des effets plus spécifiques.


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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