Full text data of IKBKE
IKBKE
(IKKE, IKKI, KIAA0151)
[Confidence: low (only semi-automatic identification from reviews)]
Inhibitor of nuclear factor kappa-B kinase subunit epsilon; I-kappa-B kinase epsilon; IKK-E; IKK-epsilon; IkBKE; 2.7.11.10 (Inducible I kappa-B kinase; IKK-i)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Inhibitor of nuclear factor kappa-B kinase subunit epsilon; I-kappa-B kinase epsilon; IKK-E; IKK-epsilon; IkBKE; 2.7.11.10 (Inducible I kappa-B kinase; IKK-i)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q14164
ID IKKE_HUMAN Reviewed; 716 AA.
AC Q14164; D3DT78; Q3B754; Q3KR43; Q5JTS6;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit epsilon;
DE Short=I-kappa-B kinase epsilon;
DE Short=IKK-E;
DE Short=IKK-epsilon;
DE Short=IkBKE;
DE EC=2.7.11.10;
DE AltName: Full=Inducible I kappa-B kinase;
DE Short=IKK-i;
GN Name=IKBKE; Synonyms=IKKE, IKKI, KIAA0151;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF LYS-38;
RP GLU-168 AND SER-172.
RX PubMed=10421793; DOI=10.1093/intimm/11.8.1357;
RA Shimada T., Kawai T., Takeda K., Matsumoto M., Inoue J., Tatsumi Y.,
RA Kanamaru A., Akira S.;
RT "IKK-i, a novel lipopolysaccharide-inducible kinase that is related to
RT IkappaB kinases.";
RL Int. Immunol. 11:1357-1362(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Leukocyte;
RX PubMed=10882136; DOI=10.1016/S1097-2765(00)80445-1;
RA Peters R.T., Liao S.-M., Maniatis T.;
RT "IKK epsilon is part of a novel PMA-inducible IkappaB kinase
RT complex.";
RL Mol. Cell 5:513-522(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV.
RT The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-128; THR-371;
RP ASP-515; MET-543; VAL-602 AND LEU-713.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH AZI2.
RX PubMed=14560022; DOI=10.1128/MCB.23.21.7780-7793.2003;
RA Fujita F., Taniguchi Y., Kato T., Narita Y., Furuya A., Ogawa T.,
RA Sakurai H., Joh T., Itoh M., Delhase M., Karin M., Nakanishi M.;
RT "Identification of NAP1, a regulatory subunit of IkappaB kinase-
RT related kinases that potentiates NF-kappaB signaling.";
RL Mol. Cell. Biol. 23:7780-7793(2003).
RN [9]
RP INTERACTION WITH TICAM1.
RX PubMed=14739303; DOI=10.1074/jbc.M311629200;
RA Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.;
RT "Mechanisms of the TRIF-induced interferon-stimulated response element
RT and NF-kappaB activation and apoptosis pathways.";
RL J. Biol. Chem. 279:15652-15661(2004).
RN [10]
RP INTERACTION WITH SIKE1; IRF3; TICAM1 AND DDX58.
RX PubMed=16281057; DOI=10.1038/sj.emboj.7600863;
RA Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.;
RT "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-
RT triggered IRF-3 activation pathways.";
RL EMBO J. 24:4018-4028(2005).
RN [11]
RP INTERACTION WITH MAVS.
RX PubMed=16177806; DOI=10.1038/nature04193;
RA Meylan E., Curran J., Hofmann K., Moradpour D., Binder M.,
RA Bartenschlager R., Tschopp J.;
RT "Cardif is an adaptor protein in the RIG-I antiviral pathway and is
RT targeted by hepatitis C virus.";
RL Nature 437:1167-1172(2005).
RN [12]
RP INTERACTION WITH CYLD.
RX PubMed=18636086; DOI=10.1038/embor.2008.136;
RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A.,
RA Cardenas W.B., Yount J.S., Moran T.M., Basler C.F., Komuro A.,
RA Horvath C.M., Xavier R., Ting A.T.;
RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated
RT antiviral response.";
RL EMBO Rep. 9:930-936(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-664, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP FUNCTION, INTERACTION WITH TOPORS, SUMOYLATION AT LYS-231 BY TOPORS,
RP DESUMOYLATION BY SENP1, MUTAGENESIS OF LYS-231, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20188669; DOI=10.1016/j.molcel.2010.01.018;
RA Renner F., Moreno R., Schmitz M.L.;
RT "SUMOylation-dependent localization of IKKepsilon in PML nuclear
RT bodies is essential for protection against DNA-damage-triggered cell
RT death.";
RL Mol. Cell 37:503-515(2010).
RN [15]
RP FUNCTION, AND PHOSPHORYLATION BY IKBKB/IKKB.
RX PubMed=21138416; DOI=10.1042/BJ20101701;
RA Clark K., Peggie M., Plater L., Sorcek R.J., Young E.R., Madwed J.B.,
RA Hough J., McIver E.G., Cohen P.;
RT "Novel cross-talk within the IKK family controls innate immunity.";
RL Biochem. J. 434:93-104(2011).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-371; MET-483; VAL-602; GLU-660 AND
RP LEU-713.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Phosphorylates inhibitors of NF-kappa-B thus leading to
CC the dissociation of the inhibitor/NF-kappa-B complex and
CC ultimately the degradation of the inhibitor. May play a special
CC role in the immune response. Protects cells against DNA damage-
CC induced cell death.
CC -!- CATALYTIC ACTIVITY: ATP + [I-kappa-B protein] = ADP + [I-kappa-B
CC phosphoprotein].
CC -!- SUBUNIT: May interact with MAVS/IPS1. Interacts with AZI2.
CC Interacts with SIKE1. Interacts with TICAM1/TRIF, IRF3 and
CC DDX58/RIG-I, interactions are disrupted by the interaction between
CC IKBKE and SIKE1. Interacts with TOPORS; induced by DNA damage.
CC Interacts with CYLD.
CC -!- INTERACTION:
CC K7Y1A2:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-8788634;
CC P27958:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-6919131;
CC O00571:DDX3X; NbExp=4; IntAct=EBI-307369, EBI-353779;
CC Q7Z434:MAVS; NbExp=2; IntAct=EBI-307369, EBI-995373;
CC Q92844:TANK; NbExp=2; IntAct=EBI-307369, EBI-356349;
CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-307369, EBI-356402;
CC A7MCY6:TBKBP1; NbExp=3; IntAct=EBI-307369, EBI-359969;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body.
CC Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS-
CC dependent.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14164-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q14164-2; Sequence=VSP_044305;
CC -!- TISSUE SPECIFICITY: Highly expressed in spleen followed by thymus,
CC peripheral blood leukocytes, pancreas, placenta. Weakly expressed
CC in lung, kidney, prostate, ovary and colon.
CC -!- PTM: Autophosphorylated and phosphorylated by IKBKB/IKKB.
CC -!- PTM: Sumoylation by TOPORS upon DNA damage is required for
CC protection of cells against DNA damage-induced cell death.
CC Desumoylated by SENP1.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr
CC protein kinase family. I-kappa-B kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA09772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ikbke/";
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DR EMBL; D63485; BAA09772.2; ALT_INIT; mRNA.
DR EMBL; AB016590; BAA85155.1; -; mRNA.
DR EMBL; AF241789; AAF45307.1; -; mRNA.
DR EMBL; DQ667176; ABG25921.1; -; Genomic_DNA.
DR EMBL; AL354681; CAI15250.1; -; Genomic_DNA.
DR EMBL; CH471100; EAW93549.1; -; Genomic_DNA.
DR EMBL; BC105923; AAI05924.1; -; mRNA.
DR EMBL; BC105924; AAI05925.1; -; mRNA.
DR EMBL; BC107812; AAI07813.1; -; mRNA.
DR RefSeq; NP_001180250.1; NM_001193321.1.
DR RefSeq; NP_001180251.1; NM_001193322.1.
DR RefSeq; NP_054721.1; NM_014002.3.
DR RefSeq; XP_005273413.1; XM_005273356.1.
DR RefSeq; XP_005277578.1; XM_005277521.1.
DR UniGene; Hs.321045; -.
DR ProteinModelPortal; Q14164; -.
DR SMR; Q14164; 2-621.
DR DIP; DIP-27530N; -.
DR IntAct; Q14164; 15.
DR MINT; MINT-1132084; -.
DR STRING; 9606.ENSP00000356087; -.
DR BindingDB; Q14164; -.
DR ChEMBL; CHEMBL3529; -.
DR GuidetoPHARMACOLOGY; 2040; -.
DR PhosphoSite; Q14164; -.
DR DMDM; 14548079; -.
DR PaxDb; Q14164; -.
DR PRIDE; Q14164; -.
DR DNASU; 9641; -.
DR Ensembl; ENST00000367120; ENSP00000356087; ENSG00000143466.
DR Ensembl; ENST00000537984; ENSP00000444529; ENSG00000143466.
DR Ensembl; ENST00000581977; ENSP00000464030; ENSG00000263528.
DR Ensembl; ENST00000584998; ENSP00000462396; ENSG00000263528.
DR GeneID; 9641; -.
DR KEGG; hsa:9641; -.
DR UCSC; uc001hdz.2; human.
DR CTD; 9641; -.
DR GeneCards; GC01P206643; -.
DR H-InvDB; HIX0116011; -.
DR HGNC; HGNC:14552; IKBKE.
DR HPA; CAB025983; -.
DR HPA; HPA015788; -.
DR MIM; 605048; gene.
DR neXtProt; NX_Q14164; -.
DR PharmGKB; PA134962294; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000220867; -.
DR HOVERGEN; HBG008494; -.
DR InParanoid; Q14164; -.
DR KO; K07211; -.
DR OMA; HIYIHAH; -.
DR OrthoDB; EOG7Z95KH; -.
DR PhylomeDB; Q14164; -.
DR BRENDA; 2.7.11.10; 2681.
DR Reactome; REACT_6900; Immune System.
DR SABIO-RK; Q14164; -.
DR SignaLink; Q14164; -.
DR ChiTaRS; IKBKE; human.
DR GeneWiki; IKBKE; -.
DR GenomeRNAi; 9641; -.
DR NextBio; 36191; -.
DR PRO; PR:Q14164; -.
DR Bgee; Q14164; -.
DR CleanEx; HS_IKBKE; -.
DR Genevestigator; Q14164; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0008384; F:IkappaB kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:UniProtKB.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Complete proteome; Cytoplasm;
KW DNA damage; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1 716 Inhibitor of nuclear factor kappa-B
FT kinase subunit epsilon.
FT /FTId=PRO_0000086017.
FT DOMAIN 9 315 Protein kinase.
FT NP_BIND 15 23 ATP (By similarity).
FT REGION 436 457 Leucine-zipper.
FT ACT_SITE 135 135 Proton acceptor (By similarity).
FT BINDING 38 38 ATP (By similarity).
FT MOD_RES 172 172 Phosphoserine; by IKKB.
FT MOD_RES 664 664 Phosphoserine.
FT CROSSLNK 231 231 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO1).
FT VAR_SEQ 1 85 Missing (in isoform 2).
FT /FTId=VSP_044305.
FT VARIANT 128 128 E -> K (in dbSNP:rs41296028).
FT /FTId=VAR_038816.
FT VARIANT 371 371 A -> T (in dbSNP:rs17021877).
FT /FTId=VAR_038817.
FT VARIANT 483 483 T -> M (in dbSNP:rs52817862).
FT /FTId=VAR_040571.
FT VARIANT 515 515 E -> D (in dbSNP:rs41299015).
FT /FTId=VAR_038818.
FT VARIANT 543 543 I -> M (in dbSNP:rs41299037).
FT /FTId=VAR_038819.
FT VARIANT 602 602 A -> V (in dbSNP:rs12059562).
FT /FTId=VAR_038820.
FT VARIANT 660 660 G -> E (in dbSNP:rs55822317).
FT /FTId=VAR_040572.
FT VARIANT 713 713 P -> L (in dbSNP:rs3748022).
FT /FTId=VAR_019989.
FT MUTAGEN 38 38 K->A: Loss of kinase activity and loss of
FT nuclear import.
FT MUTAGEN 168 168 E->A: Slight decrease of kinase activity.
FT MUTAGEN 172 172 S->A: Loss of autophosphorylation and of
FT kinase activity.
FT MUTAGEN 172 172 S->E: Decrease in kinase activity.
FT MUTAGEN 231 231 K->R: Loss of sumoylation and loss of
FT targeting to nuclear bodies.
FT CONFLICT 187 187 R -> Q (in Ref. 7; AAI05925).
SQ SEQUENCE 716 AA; 80462 MW; 3E5FBE5840734D81 CRC64;
MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR
KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE
KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA
ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV
LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG
AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV
AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI
QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY
QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKLLEELS HQLLQDRAKG
AQASPPPIAP YPSPTRKDLL LHMQELCEGM KLLASDLLDN NRIIERLNRV PAPPDV
//
ID IKKE_HUMAN Reviewed; 716 AA.
AC Q14164; D3DT78; Q3B754; Q3KR43; Q5JTS6;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit epsilon;
DE Short=I-kappa-B kinase epsilon;
DE Short=IKK-E;
DE Short=IKK-epsilon;
DE Short=IkBKE;
DE EC=2.7.11.10;
DE AltName: Full=Inducible I kappa-B kinase;
DE Short=IKK-i;
GN Name=IKBKE; Synonyms=IKKE, IKKI, KIAA0151;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF LYS-38;
RP GLU-168 AND SER-172.
RX PubMed=10421793; DOI=10.1093/intimm/11.8.1357;
RA Shimada T., Kawai T., Takeda K., Matsumoto M., Inoue J., Tatsumi Y.,
RA Kanamaru A., Akira S.;
RT "IKK-i, a novel lipopolysaccharide-inducible kinase that is related to
RT IkappaB kinases.";
RL Int. Immunol. 11:1357-1362(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Leukocyte;
RX PubMed=10882136; DOI=10.1016/S1097-2765(00)80445-1;
RA Peters R.T., Liao S.-M., Maniatis T.;
RT "IKK epsilon is part of a novel PMA-inducible IkappaB kinase
RT complex.";
RL Mol. Cell 5:513-522(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV.
RT The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-128; THR-371;
RP ASP-515; MET-543; VAL-602 AND LEU-713.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH AZI2.
RX PubMed=14560022; DOI=10.1128/MCB.23.21.7780-7793.2003;
RA Fujita F., Taniguchi Y., Kato T., Narita Y., Furuya A., Ogawa T.,
RA Sakurai H., Joh T., Itoh M., Delhase M., Karin M., Nakanishi M.;
RT "Identification of NAP1, a regulatory subunit of IkappaB kinase-
RT related kinases that potentiates NF-kappaB signaling.";
RL Mol. Cell. Biol. 23:7780-7793(2003).
RN [9]
RP INTERACTION WITH TICAM1.
RX PubMed=14739303; DOI=10.1074/jbc.M311629200;
RA Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.;
RT "Mechanisms of the TRIF-induced interferon-stimulated response element
RT and NF-kappaB activation and apoptosis pathways.";
RL J. Biol. Chem. 279:15652-15661(2004).
RN [10]
RP INTERACTION WITH SIKE1; IRF3; TICAM1 AND DDX58.
RX PubMed=16281057; DOI=10.1038/sj.emboj.7600863;
RA Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.;
RT "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-
RT triggered IRF-3 activation pathways.";
RL EMBO J. 24:4018-4028(2005).
RN [11]
RP INTERACTION WITH MAVS.
RX PubMed=16177806; DOI=10.1038/nature04193;
RA Meylan E., Curran J., Hofmann K., Moradpour D., Binder M.,
RA Bartenschlager R., Tschopp J.;
RT "Cardif is an adaptor protein in the RIG-I antiviral pathway and is
RT targeted by hepatitis C virus.";
RL Nature 437:1167-1172(2005).
RN [12]
RP INTERACTION WITH CYLD.
RX PubMed=18636086; DOI=10.1038/embor.2008.136;
RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A.,
RA Cardenas W.B., Yount J.S., Moran T.M., Basler C.F., Komuro A.,
RA Horvath C.M., Xavier R., Ting A.T.;
RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated
RT antiviral response.";
RL EMBO Rep. 9:930-936(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-664, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP FUNCTION, INTERACTION WITH TOPORS, SUMOYLATION AT LYS-231 BY TOPORS,
RP DESUMOYLATION BY SENP1, MUTAGENESIS OF LYS-231, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20188669; DOI=10.1016/j.molcel.2010.01.018;
RA Renner F., Moreno R., Schmitz M.L.;
RT "SUMOylation-dependent localization of IKKepsilon in PML nuclear
RT bodies is essential for protection against DNA-damage-triggered cell
RT death.";
RL Mol. Cell 37:503-515(2010).
RN [15]
RP FUNCTION, AND PHOSPHORYLATION BY IKBKB/IKKB.
RX PubMed=21138416; DOI=10.1042/BJ20101701;
RA Clark K., Peggie M., Plater L., Sorcek R.J., Young E.R., Madwed J.B.,
RA Hough J., McIver E.G., Cohen P.;
RT "Novel cross-talk within the IKK family controls innate immunity.";
RL Biochem. J. 434:93-104(2011).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-371; MET-483; VAL-602; GLU-660 AND
RP LEU-713.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Phosphorylates inhibitors of NF-kappa-B thus leading to
CC the dissociation of the inhibitor/NF-kappa-B complex and
CC ultimately the degradation of the inhibitor. May play a special
CC role in the immune response. Protects cells against DNA damage-
CC induced cell death.
CC -!- CATALYTIC ACTIVITY: ATP + [I-kappa-B protein] = ADP + [I-kappa-B
CC phosphoprotein].
CC -!- SUBUNIT: May interact with MAVS/IPS1. Interacts with AZI2.
CC Interacts with SIKE1. Interacts with TICAM1/TRIF, IRF3 and
CC DDX58/RIG-I, interactions are disrupted by the interaction between
CC IKBKE and SIKE1. Interacts with TOPORS; induced by DNA damage.
CC Interacts with CYLD.
CC -!- INTERACTION:
CC K7Y1A2:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-8788634;
CC P27958:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-6919131;
CC O00571:DDX3X; NbExp=4; IntAct=EBI-307369, EBI-353779;
CC Q7Z434:MAVS; NbExp=2; IntAct=EBI-307369, EBI-995373;
CC Q92844:TANK; NbExp=2; IntAct=EBI-307369, EBI-356349;
CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-307369, EBI-356402;
CC A7MCY6:TBKBP1; NbExp=3; IntAct=EBI-307369, EBI-359969;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body.
CC Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS-
CC dependent.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14164-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q14164-2; Sequence=VSP_044305;
CC -!- TISSUE SPECIFICITY: Highly expressed in spleen followed by thymus,
CC peripheral blood leukocytes, pancreas, placenta. Weakly expressed
CC in lung, kidney, prostate, ovary and colon.
CC -!- PTM: Autophosphorylated and phosphorylated by IKBKB/IKKB.
CC -!- PTM: Sumoylation by TOPORS upon DNA damage is required for
CC protection of cells against DNA damage-induced cell death.
CC Desumoylated by SENP1.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr
CC protein kinase family. I-kappa-B kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA09772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ikbke/";
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DR EMBL; D63485; BAA09772.2; ALT_INIT; mRNA.
DR EMBL; AB016590; BAA85155.1; -; mRNA.
DR EMBL; AF241789; AAF45307.1; -; mRNA.
DR EMBL; DQ667176; ABG25921.1; -; Genomic_DNA.
DR EMBL; AL354681; CAI15250.1; -; Genomic_DNA.
DR EMBL; CH471100; EAW93549.1; -; Genomic_DNA.
DR EMBL; BC105923; AAI05924.1; -; mRNA.
DR EMBL; BC105924; AAI05925.1; -; mRNA.
DR EMBL; BC107812; AAI07813.1; -; mRNA.
DR RefSeq; NP_001180250.1; NM_001193321.1.
DR RefSeq; NP_001180251.1; NM_001193322.1.
DR RefSeq; NP_054721.1; NM_014002.3.
DR RefSeq; XP_005273413.1; XM_005273356.1.
DR RefSeq; XP_005277578.1; XM_005277521.1.
DR UniGene; Hs.321045; -.
DR ProteinModelPortal; Q14164; -.
DR SMR; Q14164; 2-621.
DR DIP; DIP-27530N; -.
DR IntAct; Q14164; 15.
DR MINT; MINT-1132084; -.
DR STRING; 9606.ENSP00000356087; -.
DR BindingDB; Q14164; -.
DR ChEMBL; CHEMBL3529; -.
DR GuidetoPHARMACOLOGY; 2040; -.
DR PhosphoSite; Q14164; -.
DR DMDM; 14548079; -.
DR PaxDb; Q14164; -.
DR PRIDE; Q14164; -.
DR DNASU; 9641; -.
DR Ensembl; ENST00000367120; ENSP00000356087; ENSG00000143466.
DR Ensembl; ENST00000537984; ENSP00000444529; ENSG00000143466.
DR Ensembl; ENST00000581977; ENSP00000464030; ENSG00000263528.
DR Ensembl; ENST00000584998; ENSP00000462396; ENSG00000263528.
DR GeneID; 9641; -.
DR KEGG; hsa:9641; -.
DR UCSC; uc001hdz.2; human.
DR CTD; 9641; -.
DR GeneCards; GC01P206643; -.
DR H-InvDB; HIX0116011; -.
DR HGNC; HGNC:14552; IKBKE.
DR HPA; CAB025983; -.
DR HPA; HPA015788; -.
DR MIM; 605048; gene.
DR neXtProt; NX_Q14164; -.
DR PharmGKB; PA134962294; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000220867; -.
DR HOVERGEN; HBG008494; -.
DR InParanoid; Q14164; -.
DR KO; K07211; -.
DR OMA; HIYIHAH; -.
DR OrthoDB; EOG7Z95KH; -.
DR PhylomeDB; Q14164; -.
DR BRENDA; 2.7.11.10; 2681.
DR Reactome; REACT_6900; Immune System.
DR SABIO-RK; Q14164; -.
DR SignaLink; Q14164; -.
DR ChiTaRS; IKBKE; human.
DR GeneWiki; IKBKE; -.
DR GenomeRNAi; 9641; -.
DR NextBio; 36191; -.
DR PRO; PR:Q14164; -.
DR Bgee; Q14164; -.
DR CleanEx; HS_IKBKE; -.
DR Genevestigator; Q14164; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0008384; F:IkappaB kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:UniProtKB.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Complete proteome; Cytoplasm;
KW DNA damage; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1 716 Inhibitor of nuclear factor kappa-B
FT kinase subunit epsilon.
FT /FTId=PRO_0000086017.
FT DOMAIN 9 315 Protein kinase.
FT NP_BIND 15 23 ATP (By similarity).
FT REGION 436 457 Leucine-zipper.
FT ACT_SITE 135 135 Proton acceptor (By similarity).
FT BINDING 38 38 ATP (By similarity).
FT MOD_RES 172 172 Phosphoserine; by IKKB.
FT MOD_RES 664 664 Phosphoserine.
FT CROSSLNK 231 231 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO1).
FT VAR_SEQ 1 85 Missing (in isoform 2).
FT /FTId=VSP_044305.
FT VARIANT 128 128 E -> K (in dbSNP:rs41296028).
FT /FTId=VAR_038816.
FT VARIANT 371 371 A -> T (in dbSNP:rs17021877).
FT /FTId=VAR_038817.
FT VARIANT 483 483 T -> M (in dbSNP:rs52817862).
FT /FTId=VAR_040571.
FT VARIANT 515 515 E -> D (in dbSNP:rs41299015).
FT /FTId=VAR_038818.
FT VARIANT 543 543 I -> M (in dbSNP:rs41299037).
FT /FTId=VAR_038819.
FT VARIANT 602 602 A -> V (in dbSNP:rs12059562).
FT /FTId=VAR_038820.
FT VARIANT 660 660 G -> E (in dbSNP:rs55822317).
FT /FTId=VAR_040572.
FT VARIANT 713 713 P -> L (in dbSNP:rs3748022).
FT /FTId=VAR_019989.
FT MUTAGEN 38 38 K->A: Loss of kinase activity and loss of
FT nuclear import.
FT MUTAGEN 168 168 E->A: Slight decrease of kinase activity.
FT MUTAGEN 172 172 S->A: Loss of autophosphorylation and of
FT kinase activity.
FT MUTAGEN 172 172 S->E: Decrease in kinase activity.
FT MUTAGEN 231 231 K->R: Loss of sumoylation and loss of
FT targeting to nuclear bodies.
FT CONFLICT 187 187 R -> Q (in Ref. 7; AAI05925).
SQ SEQUENCE 716 AA; 80462 MW; 3E5FBE5840734D81 CRC64;
MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR
KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE
KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA
ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV
LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG
AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV
AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI
QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY
QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKLLEELS HQLLQDRAKG
AQASPPPIAP YPSPTRKDLL LHMQELCEGM KLLASDLLDN NRIIERLNRV PAPPDV
//
MIM
605048
*RECORD*
*FIELD* NO
605048
*FIELD* TI
*605048 INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE
OF, EPSILON; IKBKE
read more;;I-KAPPA-B KINASE-EPSILON; IKKE;;
IKK-EPSILON;;
INDUCIBLE I-KAPPA-B KINASE; IKKI;;
KIAA0151
*FIELD* TX
DESCRIPTION
IKBKE is a noncanonical I-kappa-B (see 164008) kinase (IKK) that is
essential for regulating antiviral signaling pathways. IKBKE has also
been identified as a breast cancer (114480) oncogene and is amplified
and overexpressed in over 30% of breast carcinomas and breast cancer
cell lines (Hutti et al., 2009).
CLONING
By screening a lipopolysaccharide (LPS)-stimulated mouse macrophage cell
line with the suppression subtractive hybridization technique, Shimada
et al. (1999) obtained a cDNA that they termed IKKI (inducible I-kappa-B
kinase), a homolog of the human KIAA0151 cDNA identified by Nagase et
al. (1995). Sequence analysis predicted that the 716-amino acid protein
contains an N-terminal serine/threonine kinase domain and C-terminal
leucine zipper and helix-loop-helix domains. Northern blot analysis
revealed expression of a 4.0-kb transcript in spleen, thymus, peripheral
blood leukocytes, pancreas, and placenta, with low expression in lung,
kidney, prostate, ovary, and colon.
Independently, Peters et al. (2000) reported the identification of a
novel PMA-inducible I-kappa-B kinase complex. They characterized one
kinase from this complex, which they designated IKK-epsilon (IKBKE). The
IKBKE protein shows 33% and 31% amino acid identity with IKBKA (600664)
and IKBKB (603258), respectively, within the kinase domain and 27% amino
acid identity with each throughout the entire sequence. Northern blot
analysis revealed that IKBKE is expressed in many tissues as a 3.2-kb
transcript, but is particularly abundant in thymus, spleen, and
peripheral blood leukocytes.
GENE FUNCTION
Shimada et al. (1999) performed functional analyses showing that IKKI
preferentially phosphorylates ser36 rather than ser32 of I-kappa-B-alpha
(NFKBIA; 164008). Whereas TNFA (191160) and IL1B (147720) enhance the
kinase activity of IKBKA and IKBKB, they do not enhance IKKI kinase
activity.
Peters et al. (2000) found that although recombinant IKK-epsilon
directly phosphorylates only ser36 of I-kappa-B-alpha, the PMA-activated
endogenous IKK complex phosphorylates both critical serine (ser32 and
ser36) residues. Remarkably, this activity appears to be due to the
presence of a distinct kinase in this complex. A dominant-negative
mutant of IKK-epsilon (lys38 to ala) blocks induction of NF-kappa-B by
both PMA and activation of the T-cell receptor but has no effect on the
activation of NF-kappa-B by TNF or IL1. These observations indicate that
the activation of NF-kappa-B requires multiple distinct I-kappa-B kinase
complexes that respond to both overlapping and discrete signaling
pathways.
Sharma et al. (2003) demonstrated that IKKE and TANK-binding kinase-1
(TBK1; 604834) are components of the virus-activated kinase (VAK) that
phosphorylate IRF3 (603734) and IRF7 (605047). They demonstrated an
essential role for an IKK-related kinase pathway in triggering the host
antiviral response to viral infection. Sharma et al. (2003) demonstrated
that expression of IKKE or TBK1 is sufficient to induce phosphorylation
of IRF3 and IRF7. This modification permits IRF3 dimerization and
translocation to the nucleus, where it induces transcription of
interferon and ISG56 genes.
By yeast 2-hybrid screening of a B-cell cDNA library, Zha et al. (2006)
found that IKKE interacted with the C terminus of RFP (TRIM27; 602165).
Coimmunoprecipitation experiments showed that RFP also interacted with
TBK1, IKKA, and IKKB. Immunofluorescence and confocal microscopy
demonstrated primarily cytoplasmic expression of RFP and IKKE. In vitro
kinase assays showed that RFP was strongly phosphorylated by IKKE and
TBK1, but only weakly by IKKA and IKKB. RFP inhibited NFKB (see 164011)
and IFN-stimulated response element activation triggered by IKK
overexpression or by cytokine or viral infection pathways. Zha et al.
(2006) concluded that RFP negatively regulates signaling involved in the
antiviral response and inflammation by targeting IKKs.
Using a proteomic and bioinformatic approach, Hutti et al. (2009)
identified the optimal motif for phosphorylation by IKK-epsilon and
identified a number of putative substrates, including several components
of inflammatory and/or oncogenic signaling pathways. One predicted
substrate, CYLD (605018), is a deubiquitinase that functions as a tumor
suppressor. CYLD was phosphorylated by IKK-epsilon on ser418 in vitro
and in vivo. Phosphorylation of CYLD at ser418 decreased its
deubiquitinase activity and was necessary for IKK-epsilon-dependent
transformation in NIH-3T3 mouse fibroblasts.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the
KIAA0151 gene to chromosome 1 (TMAP T95631).
ANIMAL MODEL
TenOever et al. (2007) reported that although mice lacking Ikke produced
normal amounts of interferon-beta (IFNB; 147640), they were
hypersusceptible to viral infection because of a defect in the IFN
signaling pathway. Specifically, a subset of type I IFN-stimulated genes
were not activated in the absence of Ikke because the
interferon-stimulated gene factor-3 complex (ISGF3; see 147574) did not
bind to promoter elements of the affected genes. TenOever et al. (2007)
demonstrated that Ikke was activated by Ifnb and that Ikke directly
phosphorylated signal transducer and activator of transcription-1
(STAT1; 600555), a component of Isgf3. They concluded that IKKE plays a
critical role in the IFN-inducible antiviral transcriptional response.
Obesity produces a state of chronic low-grade inflammation accompanied
by increased circulating levels of proinflammatory cytokines, many of
which block insulin action. Chiang et al. (2009) found that a high-fat
diet induced expression of Ikke in both liver and white adipose tissue
in mice. Ikke-knockout mice were protected from diet-induced obesity,
liver and adipose inflammation, hepatic steatosis, and insulin
resistance.
*FIELD* RF
1. Chiang, S.-H.; Bazuine, M.; Lumeng, C. N.; Geletka, L. M.; Mowers,
J.; White, N. M.; Ma, J.-T.; Zhou, J.; Qi, N.; Westcott, D.; Delproposto,
J. B.; Blackwell, T. S.; Yull, F. E.; Saltiel, A. R.: The protein
kinase IKK-epsilon regulates energy balance in obese mice. Cell 138:
961-975, 2009.
2. Hutti, J. E.; Shen, R. R.; Abbott, D. W.; Zhou, A. Y.; Sprott,
K. M.; Asara, J. M.; Hahn, W. C.; Cantley, L. C.: Phosphorylation
of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon
promotes cell transformation. Molec. Cell 34: 461-472, 2009.
3. Nagase, T.; Seki, N.; Tanaka, A.; Ishikawa, K.; Nomura, N.: Prediction
of the coding sequences of unidentified human genes. IV. The coding
sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995.
4. Peters, R. T.; Liao, S.-M.; Maniatis, T.: IKK-epsilon is part
of a novel PMA-inducible I-kappa-B kinase complex. Molec. Cell 5:
513-522, 2000.
5. Sharma, S.; tenOever, B. R.; Grandvaux, N.; Zhou, G.-P.; Lin, R.;
Hiscott, J.: Triggering the interferon antiviral response through
an IKK-related pathway. Science 300: 1148-1151, 2003.
6. Shimada, T.; Kawai, T.; Takeda, K.; Matsumoto, M.; Inoue, J.; Tatsumi,
Y.; Kanamaru, A.; Akira, S.: IKK-i, a novel lipopolysaccharide-inducible
kinase that is related to I-kappa-B kinases. Int. Immun. 11: 1357-1362,
1999.
7. tenOever, B. R.; Ng, S.-L.; Chua, M. A.; McWhirter, S. M.; Garcia-Sastre,
A.; Maniatis, T.: Multiple functions of the IKK-related kinase IKK-epsilon
in interferon-mediated antiviral immunity. Science 315: 1274-1278,
2007.
8. Zha, J.; Han, K.-J.; Xu, L.-G.; He, W.; Zhou, Q.; Chen, D.; Zhai,
Z.; Shu, H.-B.: The Ret finger protein inhibits signaling mediated
by the noncanonical and canonical I-kappa-B kinase family members. J.
Immun. 176: 1072-1080, 2006.
*FIELD* CN
Matthew B. Gross - updated: 10/29/2009
Patricia A. Hartz - updated: 10/7/2009
Ada Hamosh - updated: 4/17/2007
Paul J. Converse - updated: 11/2/2006
Ada Hamosh - updated: 6/10/2003
Paul J. Converse - updated: 7/21/2000
*FIELD* CD
Stylianos E. Antonarakis: 6/14/2000
*FIELD* ED
mgross: 10/29/2009
mgross: 10/26/2009
terry: 10/7/2009
alopez: 4/18/2007
terry: 4/17/2007
mgross: 11/6/2006
terry: 11/2/2006
alopez: 6/11/2003
terry: 6/10/2003
carol: 12/3/2002
carol: 7/21/2000
carol: 6/15/2000
carol: 6/14/2000
*RECORD*
*FIELD* NO
605048
*FIELD* TI
*605048 INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE
OF, EPSILON; IKBKE
read more;;I-KAPPA-B KINASE-EPSILON; IKKE;;
IKK-EPSILON;;
INDUCIBLE I-KAPPA-B KINASE; IKKI;;
KIAA0151
*FIELD* TX
DESCRIPTION
IKBKE is a noncanonical I-kappa-B (see 164008) kinase (IKK) that is
essential for regulating antiviral signaling pathways. IKBKE has also
been identified as a breast cancer (114480) oncogene and is amplified
and overexpressed in over 30% of breast carcinomas and breast cancer
cell lines (Hutti et al., 2009).
CLONING
By screening a lipopolysaccharide (LPS)-stimulated mouse macrophage cell
line with the suppression subtractive hybridization technique, Shimada
et al. (1999) obtained a cDNA that they termed IKKI (inducible I-kappa-B
kinase), a homolog of the human KIAA0151 cDNA identified by Nagase et
al. (1995). Sequence analysis predicted that the 716-amino acid protein
contains an N-terminal serine/threonine kinase domain and C-terminal
leucine zipper and helix-loop-helix domains. Northern blot analysis
revealed expression of a 4.0-kb transcript in spleen, thymus, peripheral
blood leukocytes, pancreas, and placenta, with low expression in lung,
kidney, prostate, ovary, and colon.
Independently, Peters et al. (2000) reported the identification of a
novel PMA-inducible I-kappa-B kinase complex. They characterized one
kinase from this complex, which they designated IKK-epsilon (IKBKE). The
IKBKE protein shows 33% and 31% amino acid identity with IKBKA (600664)
and IKBKB (603258), respectively, within the kinase domain and 27% amino
acid identity with each throughout the entire sequence. Northern blot
analysis revealed that IKBKE is expressed in many tissues as a 3.2-kb
transcript, but is particularly abundant in thymus, spleen, and
peripheral blood leukocytes.
GENE FUNCTION
Shimada et al. (1999) performed functional analyses showing that IKKI
preferentially phosphorylates ser36 rather than ser32 of I-kappa-B-alpha
(NFKBIA; 164008). Whereas TNFA (191160) and IL1B (147720) enhance the
kinase activity of IKBKA and IKBKB, they do not enhance IKKI kinase
activity.
Peters et al. (2000) found that although recombinant IKK-epsilon
directly phosphorylates only ser36 of I-kappa-B-alpha, the PMA-activated
endogenous IKK complex phosphorylates both critical serine (ser32 and
ser36) residues. Remarkably, this activity appears to be due to the
presence of a distinct kinase in this complex. A dominant-negative
mutant of IKK-epsilon (lys38 to ala) blocks induction of NF-kappa-B by
both PMA and activation of the T-cell receptor but has no effect on the
activation of NF-kappa-B by TNF or IL1. These observations indicate that
the activation of NF-kappa-B requires multiple distinct I-kappa-B kinase
complexes that respond to both overlapping and discrete signaling
pathways.
Sharma et al. (2003) demonstrated that IKKE and TANK-binding kinase-1
(TBK1; 604834) are components of the virus-activated kinase (VAK) that
phosphorylate IRF3 (603734) and IRF7 (605047). They demonstrated an
essential role for an IKK-related kinase pathway in triggering the host
antiviral response to viral infection. Sharma et al. (2003) demonstrated
that expression of IKKE or TBK1 is sufficient to induce phosphorylation
of IRF3 and IRF7. This modification permits IRF3 dimerization and
translocation to the nucleus, where it induces transcription of
interferon and ISG56 genes.
By yeast 2-hybrid screening of a B-cell cDNA library, Zha et al. (2006)
found that IKKE interacted with the C terminus of RFP (TRIM27; 602165).
Coimmunoprecipitation experiments showed that RFP also interacted with
TBK1, IKKA, and IKKB. Immunofluorescence and confocal microscopy
demonstrated primarily cytoplasmic expression of RFP and IKKE. In vitro
kinase assays showed that RFP was strongly phosphorylated by IKKE and
TBK1, but only weakly by IKKA and IKKB. RFP inhibited NFKB (see 164011)
and IFN-stimulated response element activation triggered by IKK
overexpression or by cytokine or viral infection pathways. Zha et al.
(2006) concluded that RFP negatively regulates signaling involved in the
antiviral response and inflammation by targeting IKKs.
Using a proteomic and bioinformatic approach, Hutti et al. (2009)
identified the optimal motif for phosphorylation by IKK-epsilon and
identified a number of putative substrates, including several components
of inflammatory and/or oncogenic signaling pathways. One predicted
substrate, CYLD (605018), is a deubiquitinase that functions as a tumor
suppressor. CYLD was phosphorylated by IKK-epsilon on ser418 in vitro
and in vivo. Phosphorylation of CYLD at ser418 decreased its
deubiquitinase activity and was necessary for IKK-epsilon-dependent
transformation in NIH-3T3 mouse fibroblasts.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the
KIAA0151 gene to chromosome 1 (TMAP T95631).
ANIMAL MODEL
TenOever et al. (2007) reported that although mice lacking Ikke produced
normal amounts of interferon-beta (IFNB; 147640), they were
hypersusceptible to viral infection because of a defect in the IFN
signaling pathway. Specifically, a subset of type I IFN-stimulated genes
were not activated in the absence of Ikke because the
interferon-stimulated gene factor-3 complex (ISGF3; see 147574) did not
bind to promoter elements of the affected genes. TenOever et al. (2007)
demonstrated that Ikke was activated by Ifnb and that Ikke directly
phosphorylated signal transducer and activator of transcription-1
(STAT1; 600555), a component of Isgf3. They concluded that IKKE plays a
critical role in the IFN-inducible antiviral transcriptional response.
Obesity produces a state of chronic low-grade inflammation accompanied
by increased circulating levels of proinflammatory cytokines, many of
which block insulin action. Chiang et al. (2009) found that a high-fat
diet induced expression of Ikke in both liver and white adipose tissue
in mice. Ikke-knockout mice were protected from diet-induced obesity,
liver and adipose inflammation, hepatic steatosis, and insulin
resistance.
*FIELD* RF
1. Chiang, S.-H.; Bazuine, M.; Lumeng, C. N.; Geletka, L. M.; Mowers,
J.; White, N. M.; Ma, J.-T.; Zhou, J.; Qi, N.; Westcott, D.; Delproposto,
J. B.; Blackwell, T. S.; Yull, F. E.; Saltiel, A. R.: The protein
kinase IKK-epsilon regulates energy balance in obese mice. Cell 138:
961-975, 2009.
2. Hutti, J. E.; Shen, R. R.; Abbott, D. W.; Zhou, A. Y.; Sprott,
K. M.; Asara, J. M.; Hahn, W. C.; Cantley, L. C.: Phosphorylation
of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon
promotes cell transformation. Molec. Cell 34: 461-472, 2009.
3. Nagase, T.; Seki, N.; Tanaka, A.; Ishikawa, K.; Nomura, N.: Prediction
of the coding sequences of unidentified human genes. IV. The coding
sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995.
4. Peters, R. T.; Liao, S.-M.; Maniatis, T.: IKK-epsilon is part
of a novel PMA-inducible I-kappa-B kinase complex. Molec. Cell 5:
513-522, 2000.
5. Sharma, S.; tenOever, B. R.; Grandvaux, N.; Zhou, G.-P.; Lin, R.;
Hiscott, J.: Triggering the interferon antiviral response through
an IKK-related pathway. Science 300: 1148-1151, 2003.
6. Shimada, T.; Kawai, T.; Takeda, K.; Matsumoto, M.; Inoue, J.; Tatsumi,
Y.; Kanamaru, A.; Akira, S.: IKK-i, a novel lipopolysaccharide-inducible
kinase that is related to I-kappa-B kinases. Int. Immun. 11: 1357-1362,
1999.
7. tenOever, B. R.; Ng, S.-L.; Chua, M. A.; McWhirter, S. M.; Garcia-Sastre,
A.; Maniatis, T.: Multiple functions of the IKK-related kinase IKK-epsilon
in interferon-mediated antiviral immunity. Science 315: 1274-1278,
2007.
8. Zha, J.; Han, K.-J.; Xu, L.-G.; He, W.; Zhou, Q.; Chen, D.; Zhai,
Z.; Shu, H.-B.: The Ret finger protein inhibits signaling mediated
by the noncanonical and canonical I-kappa-B kinase family members. J.
Immun. 176: 1072-1080, 2006.
*FIELD* CN
Matthew B. Gross - updated: 10/29/2009
Patricia A. Hartz - updated: 10/7/2009
Ada Hamosh - updated: 4/17/2007
Paul J. Converse - updated: 11/2/2006
Ada Hamosh - updated: 6/10/2003
Paul J. Converse - updated: 7/21/2000
*FIELD* CD
Stylianos E. Antonarakis: 6/14/2000
*FIELD* ED
mgross: 10/29/2009
mgross: 10/26/2009
terry: 10/7/2009
alopez: 4/18/2007
terry: 4/17/2007
mgross: 11/6/2006
terry: 11/2/2006
alopez: 6/11/2003
terry: 6/10/2003
carol: 12/3/2002
carol: 7/21/2000
carol: 6/15/2000
carol: 6/14/2000