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  7. Inhibitor of nuclear factor kappa-B kinase subunit epsilon

Tchem Inhibitor of nuclear factor kappa-B kinase subunit epsilon

Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.

IKBKE is a noncanonical I-kappa-B (see MIM 164008) kinase (IKK) that is essential for regulating antiviral signaling pathways. IKBKE has also been identified as a breast cancer (MIM 114480) oncogene and is amplified and overexpressed in over 30% of breast carcinomas and breast cancer cell lines (Hutti et al., 2009 [PubMed 19481526]).[supplied by OMIM, Oct 2009]

 Comments

Property Summary

NCBI Gene PubMed Count 122
PubMed Score 43.02
PubTator Score 70.65

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (3)

Disease Target Count P-value
psoriasis 6514 2.0e-04
Disease Target Count Z-score Confidence
Carcinoma 11192 0.0 0.9

Expression

  Differential Expression (1)

Disease log2 FC p
psoriasis 2.000 2.0e-04

Synonym

Accession Q14164 D3DT78 Q3B754 Q3KR43 Q5JTS6 I-kappa-B kinase epsilon
Symbols IKKE
IKKI
IKK-E
IKK-i

Gene

IKBKE

PANTHER Protein Class (4)

  Ortholog (1)

Species Source Disease
Chimp OMA Inparanoid

 UniProt Keyword (15)

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 GO Function (6)

 GO Component (6)

 GO Process (13)

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 Compartment GO Term (46)

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 MGI Phenotype (6)

 GWAS Trait (3)

 HCA RNA Cell Line (56)

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Pathway (39)

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Protein-protein Interaction (1)

SIKE1  

Ligand (45)

Structure of CHEMBL3687168

CHEMBL3687168
pIC50 7.57

Structure of CHEMBL220090

CHEMBL220090
pIC50 7.60

Structure of CHEMBL3687155

CHEMBL3687155
pIC50 7.60

Structure of CHEMBL3687133

CHEMBL3687133
pIC50 7.60

Structure of CHEMBL3687182

CHEMBL3687182
pIC50 7.60

Structure of CHEMBL3687180

CHEMBL3687180
pIC50 7.60

Structure of CHEMBL2011933

CHEMBL2011933
pIC50 7.68

Structure of CHEMBL3682432

CHEMBL3682432
pIC50 7.68

Structure of CHEMBL3687178

CHEMBL3687178
pIC50 7.68

Structure of CHEMBL3687158

CHEMBL3687158
pIC50 7.68

Structure of CHEMBL3687148

CHEMBL3687148
pIC50 7.70

Structure of CHEMBL2011934

CHEMBL2011934
pIC50 7.70

Structure of CHEMBL3687176

CHEMBL3687176
pIC50 7.75

Structure of CHEMBL3687124

CHEMBL3687124
pIC50 7.75

Structure of CHEMBL2011941

CHEMBL2011941
pIC50 7.77

Structure of CHEMBL3687151

CHEMBL3687151
pIC50 7.82

Structure of CHEMBL3687183

CHEMBL3687183
pIC50 7.82

Structure of CHEMBL475251

CHEMBL475251
pKd 7.89

Structure of CHEMBL3687160

CHEMBL3687160
pIC50 7.89

Structure of CHEMBL3682433

CHEMBL3682433
pIC50 7.92

Gene RIF (85)

AA Sequence 

MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLRKLNHQNIVKL      1 - 70
FAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVVAGMNHLRENGIVHRDIKPGN     71 - 140
IMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYLHPDMYERAVLRKPQQKAFGVTVDLWSIGVT    141 - 210
LYHAATGSLPFIPFGGPRRNKEIMYRITTEKPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPI    211 - 280
LANILEVEQAKCWGFDQFFAETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQ    281 - 350
EYLFEGHLCVLEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLG    351 - 420
AGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSVAGTPEIQELK    421 - 490
AAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSIQQIQCCLDKMNFIYKQFKKS    491 - 560
RMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKYQASLVTHGKRMRVVHETRNHLRLVGCSVAA    561 - 630
CNTEAQGVQESLSKLLEELSHQLLQDRAKGAQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDN    631 - 700
NRIIERLNRVPAPPDV                                                          701 - 716
//

Text Mined References (128)

PMID Year Title