Protein: Inhibitor of nuclear factor kappa-B kinase subunit alpha (I-kappa-B kinase alpha) (IKK-A) (IKK-alpha) (IkBKA) (IkappaB kinase) (EC 2.7.11.10) (Conserved helix-loop-helix ubiquitous kinase) (I-kappa-B kinase 1) (IKK1) (Nuclear factor NF-kappa-B inhibitor kinase alpha) (NFKBIKA) (Q60680)
Organism: Mus musculus (Mouse)
Function: 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. Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death. Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (By similarity).
Subcellular location: Cytoplasm {ECO:0000269|PubMed:12789342}. Nucleus {ECO:0000269|PubMed:12789342}. Note=Shuttles between the cytoplasm and the nucleus.
Sequence: MERPPGLRPGAGGPWEMRERLGTGGFGNVSLYQHRELDLKIAIKSCRLELSSKNRERWCHEIQIMKKLDHANVVKACDVPEELNFLINDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKTIHKIIDLGYAKDVDQGSLCTSFVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMTGEVRFSSHLPQPNSLCSLIVEPMESWLQLMLNWDPQQRGGPIDLTLKQPRCFALMDHILNLKIVHILNMTSAKIISFLLPCDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFRKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYSEVGVIGYLEDQIMSLHTEIMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPPDHLYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGTVTPPVSAWLPPTLADREHPLTCVVTPQDGETLAQMIEENLNCLGHLSTIIREANEDQSSSLMSLDWSWLAE
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [13-294]
- IPR000719: Protein kinase domain (domain) [15-301]
- IPR051180: Inhibitor of nuclear factor kappa-B kinase (family) [10-743]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [140-152]
- IPR017441: Protein kinase, ATP binding site (binding_site) [21-44]
- IPR041185: IKBKB, scaffold dimerization domain (domain) [386-659]
- IPR046375: IKBKB, scaffold dimerization domain superfamily (homologous_superfamily) [394-667]
- IPR022007: I-kappa-kinase-beta NEMO binding domain (domain) [706-743]
Interaction partners: - TNF receptor-associated factor 6
- NF-kappa-B inhibitor alpha
- NF-kappa-B essential modulator
- Inhibitor of nuclear factor kappa-B kinase subunit beta
- TNF receptor-associated factor 3
- Nuclear factor NF-kappa-B p105 subunit
- Protein NLRC5
- Transcription factor p65
- NF-kappa-B inhibitor beta
- TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0004672 (protein kinase activity), GO:0019899 (enzyme binding), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0019902 (phosphatase binding), GO:0019903 (protein phosphatase binding)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0042592 (homeostatic process), GO:0002376 (immune system process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0042221 (response to chemical), GO:0032879 (regulation of localization), GO:0006807 (nitrogen compound metabolic process), GO:0071704 (organic substance metabolic process), GO:0048871 (multicellular organismal-level homeostasis), GO:0051050 (positive regulation of transport), GO:0044237 (cellular metabolic process), GO:0050794 (regulation of cellular process), GO:0051716 (cellular response to stimulus), GO:0065009 (regulation of molecular function), GO:0001776 (leukocyte homeostasis), GO:0007154 (cell communication), GO:0007165 (signal transduction), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0002260 (lymphocyte homeostasis), GO:0044093 (positive regulation of molecular function), GO:0051049 (regulation of transport), GO:1901564 (organonitrogen compound metabolic process), GO:0035556 (intracellular signal transduction), GO:0032409 (regulation of transporter activity), GO:0019538 (protein metabolic process), GO:0034762 (regulation of transmembrane transport), GO:0034764 (positive regulation of transmembrane transport), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0006793 (phosphorus metabolic process), GO:0048872 (homeostasis of number of cells), GO:0070887 (cellular response to chemical stimulus), GO:0032411 (positive regulation of transporter activity), GO:0043270 (positive regulation of monoatomic ion transport), GO:0007166 (cell surface receptor signaling pathway), GO:0010765 (positive regulation of sodium ion transport), GO:0034097 (response to cytokine), GO:0071310 (cellular response to organic substance), GO:0034765 (regulation of monoatomic ion transmembrane transport), GO:0001782 (B cell homeostasis), GO:0006796 (phosphate-containing compound metabolic process), GO:0036211 (protein modification process), GO:0034767 (positive regulation of monoatomic ion transmembrane transport), GO:0043412 (macromolecule modification), GO:0032414 (positive regulation of ion transmembrane transporter activity), GO:0007249 (I-kappaB kinase/NF-kappaB signaling), GO:0022898 (regulation of transmembrane transporter activity), GO:0043269 (regulation of monoatomic ion transport), GO:0019221 (cytokine-mediated signaling pathway), GO:1904064 (positive regulation of cation transmembrane transport), GO:0032412 (regulation of monoatomic ion transmembrane transporter activity), GO:0006468 (protein phosphorylation), GO:0010959 (regulation of metal ion transport), GO:0018193 (peptidyl-amino acid modification), GO:0033209 (tumor necrosis factor-mediated signaling pathway), GO:0071345 (cellular response to cytokine stimulus), GO:0016310 (phosphorylation), GO:2001259 (positive regulation of cation channel activity), GO:0034612 (response to tumor necrosis factor), GO:1904062 (regulation of monoatomic cation transmembrane transport), GO:2001257 (regulation of cation channel activity), GO:0002028 (regulation of sodium ion transport), GO:0018105 (peptidyl-serine phosphorylation), GO:0071356 (cellular response to tumor necrosis factor), GO:0018209 (peptidyl-serine modification)
Cellular Component (CC): GO:0005575 (cellular component), GO:0032991 (protein-containing complex), GO:0110165 (cellular anatomical entity), GO:0098552 (side of membrane), GO:0005622 (intracellular anatomical structure), GO:0016020 (membrane), GO:0043235 (receptor complex), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0098796 (membrane protein complex), GO:0098797 (plasma membrane protein complex), GO:0098802 (plasma membrane signaling receptor complex), GO:0098562 (cytoplasmic side of membrane), GO:0005886 (plasma membrane), GO:0009898 (cytoplasmic side of plasma membrane)