CHUK

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]

Conserved Helix-Loop-Helix Ubiquitous Kinase

Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:12789342, PubMed:15084260, PubMed:17434128, PubMed:20434986, PubMed:20501937, PubMed:21765415).

Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).

Anatomical structure morphogenesis Source: ProtInc
Antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent Source: Reactome
Cellular response to cadmium ion Source: CAFA
Cellular response to reactive oxygen species Source: CAFA
Cellular response to tumor necrosis factor Source: UniProtKB
Cellular response to virus Source: CAFA
Fc-epsilon receptor signaling pathway Source: Reactome
I-kappaB kinase/NF-kappaB signaling Source: CAFA
I-kappaB phosphorylation Source: ProtInc
Immune response Source: ProtInc
Inflammatory response Source: UniProtKB
Innate immune response Source: UniProtKB
Interleukin-1-mediated signaling pathway Source: Reactome
MyD88-independent toll-like receptor signaling pathway Source: Reactome
Negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
NIK/NF-kappaB signaling Source: CAFA
Peptidyl-serine phosphorylation Source: GO_Central
Positive regulation of I-kappaB kinase/NF-kappaB signaling Source: ARUK-UCL
Positive regulation of interferon-alpha production Source: CAFA
Positive regulation of NF-kappaB transcription factor activity Source: GO_Central
Positive regulation of transcription, DNA-templated Source: CAFA
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of tumor necrosis factor-mediated signaling pathway Source: Reactome
Response to acetate Source: Ensembl
Response to amino acid Source: Ensembl
Response to cholecystokinin Source: Ensembl
Response to drug Source: Ensembl
Response to hydroperoxide Source: Ensembl
Response to lipopolysaccharide Source: Ensembl
Response to toxic substance Source: Ensembl
Response to virus Source: UniProtKB
Rho protein signal transduction Source: Ensembl
Skeletal muscle contraction Source: Ensembl
Stimulatory C-type lectin receptor signaling pathway Source: Reactome
Stress-activated MAPK cascade Source: Reactome
Striated muscle cell differentiation Source: Ensembl
T cell receptor signaling pathway Source: Reactome
TRIF-dependent toll-like receptor signaling pathway Source: Reactome
Tumor necrosis factor-mediated signaling pathway Source: GO_Central

Nucleus; Cytoplasm. Shuttles between the cytoplasm and the nucleus.

Cocoon syndrome (COCOS):
A lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.

Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
(Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.