ID IKKB_HUMAN Reviewed; 756 AA. AC O14920; O75327; DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 10-JUL-2007, entry version 77. DE Inhibitor of nuclear factor kappa-B kinase subunit beta (EC 2.7.11.10) DE (I-kappa-B-kinase beta) (IkBKB) (IKK-beta) (IKK-B) (I-kappa-B kinase DE 2) (IKK2) (Nuclear factor NF-kappa-B inhibitor kinase beta) (NFKBIKB). GN Name=IKBKB; Synonyms=IKKB; 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, AND MUTAGENESIS OF LYS-44; SER-177 AND SER-181. RC TISSUE=Cervix carcinoma; RX MEDLINE=98008813; PubMed=9346484; DOI=10.1126/science.278.5339.860; RA Mercurio F., Zhu H., Murray B.W., Shevchenko A., Bennett B.L., RA Li J.W., Young D.B., Barbosa M., Mann M., Manning A., Rao A.; RT "IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF- RT kappaB activation."; RL Science 278:860-866(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS OF LYS-44. RX MEDLINE=98008814; PubMed=9346485; DOI=10.1126/science.278.5339.866; RA Woronicz J.D., Gao X., Cao Z., Rothe M., Goeddel D.V.; RT "IkappaB kinase-beta: NF-kappaB activation and complex formation with RT IkappaB kinase-alpha and NIK."; RL Science 278:866-869(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Heart; RX MEDLINE=99032998; PubMed=9813230; DOI=10.1016/S0378-1119(98)00462-4; RA Hu M.C.-T., Wang Y.-P.; RT "IkappaB kinase-alpha and -beta genes are coexpressed in adult and RT embryonic tissues but localized to different human chromosomes."; RL Gene 222:31-40(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND GENE MAPPING. RX MEDLINE=98438415; PubMed=9763654; RA Shindo M., Nakano H., Sakon S., Yagita H., Mihara M., Okumura K.; RT "Assignment of IkappaB kinase beta (IKBKB) to human chromosome band RT 8p12-->p11 by in situ hybridization."; RL Cytogenet. Cell Genet. 82:32-33(1998). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT TRP-554. RA Rieder M.J., Daniels R.L., da Ponte S.H., Hastings N.C., Ahearn M.O., RA Rajkumar N., Yi Q., Nickerson D.A.; RT "SeattleSNPs. NHLBI HL66682 program for genomic applications, UW- RT FHCRC, Seattle, WA (URL: http://pga.gs.washington.edu)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-256. RC TISSUE=Lung; 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 [7] RP IKK PHOSPHORYLATION. RX MEDLINE=99038238; PubMed=9819420; RA Nemoto S., DiDonato J.A., Lin A.; RT "Coordinate regulation of IkappaB kinases by mitogen-activated protein RT kinase kinase kinase 1 and NF-kappaB-inducing kinase."; RL Mol. Cell. Biol. 18:7336-7343(1998). RN [8] RP INTERACTION WITH SQSTM1; PRKCZ AND PRKCI. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [9] RP PHOSPHORYLATION AT SER-177; SER-181; SER-670; SER-672; SER-675; RP SER-682; SER-689; SER-692; SER-695; SER-697; SER-705; SER-733; SER-740 RP AND SER-750. RX MEDLINE=99212141; PubMed=10195894; DOI=10.1126/science.284.5412.309; RA Delhase M., Hayakawa M., Chen Y., Karin M.; RT "Positive and negative regulation of IkappaB kinase activity through RT IKKbeta subunit phosphorylation."; RL Science 284:309-313(1999). RN [10] RP REVIEW. RX MEDLINE=20178139; PubMed=10712233; RA Jobin C., Sartor R.B.; RT "The I kappa B/NF-kappa B system: a key determinant of mucosal RT inflammation and protection."; RL Am. J. Physiol. 278:C451-C462(2000). RN [11] RP IDENTIFICATION IN A COMPLEX WITH CREBBP; NCOA2; NCOA3; IKKA AND IKBKG. RX MEDLINE=21968797; PubMed=11971985; RX DOI=10.1128/MCB.22.10.3549-3561.2002; RA Wu R.-C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J., RA O'Malley B.W.; RT "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator RT activity by I kappa B kinase."; RL Mol. Cell. Biol. 22:3549-3561(2002). RN [12] RP INTERACTION WITH NALP2. RX PubMed=15456791; DOI=10.1074/jbc.M406741200; RA Bruey J.-M., Bruey-Sedano N., Newman R., Chandler S., Stehlik C., RA Reed J.C.; RT "PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates RT NF-kappaB and caspase-1 activation in macrophages."; RL J. Biol. Chem. 279:51897-51907(2004). RN [13] 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 [14] RP INTERACTION WITH YOPJ, AND ACETYLATION. RX PubMed=16728640; DOI=10.1126/science.1126867; RA Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., RA Orth K.; RT "Yersinia YopJ acetylates and inhibits kinase activation by blocking RT phosphorylation."; RL Science 312:1211-1214(2006). 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. Also phosphorylates CC NCOA3 (By similarity). CC -!- CATALYTIC ACTIVITY: ATP + [I-kappa-B protein] = ADP + [I-kappa-B CC phosphoprotein]. CC -!- SUBUNIT: Preferentially found as a heterodimer with IKK-alpha but CC also as a homodimer. Directly interacts with IKK-gamma/NEMO and CC TRPC4AP. The tripartite complex can also bind to MEKK1, CC MAP3K14/NIK, IKAP and IKB-alpha-p65-p50 complex. Phosphorylated CC IKB-alpha is further released from the complex. Found in a complex CC composed of NCOA2, NCOA3, IKKA, IKBKG and CREBBP. Interacts with CC SQSTM1 through PRKCZ or PRKCI. Forms an NGF-induced complex with CC IKBKB, PRKCI and TRAF6. May interact with MAVS/IPS1. Interacts CC with NALP2. Interacts with Yersinia yopJ. CC -!- INTERACTION: CC Self; NbExp=1; IntAct=EBI-81266, EBI-81266; CC O15111:CHUK; NbExp=3; IntAct=EBI-81266, EBI-81249; CC Q9Y6K9:IKBKG; NbExp=3; IntAct=EBI-81266, EBI-81279; CC Q13233:MAP3K1; NbExp=1; IntAct=EBI-81266, EBI-49776; CC Q7Z434:MAVS; NbExp=1; IntAct=EBI-81266, EBI-995373; CC Q9Y6Q9:NCOA3; NbExp=3; IntAct=EBI-81266, EBI-81196; CC P25963:NFKBIA; NbExp=1; IntAct=EBI-81266, EBI-307386; CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- TISSUE SPECIFICITY: Highly expressed in heart, placenta, skeletal CC muscle, kidney, pancreas, spleen, thymus, prostate, testis and CC peripheral blood. CC -!- PTM: Upon cytokine stimulation, phosphorylated on Ser-177 and Ser- CC 181 by MEKK1 and/or MAP3K14/NIK; which enhances activity. Once CC activated, autophosphorylates on the C-terminal serine cluster; CC which decreases activity and prevents prolonged activation of the CC inflammatory response. CC -!- PTM: Yersinia yopJ may acetylate Ser/Thr residues, preventing CC phosphorylation and activation, which blocks the I-kappa-B CC signaling pathway. CC -!- SIMILARITY: Belongs to the Ser/Thr protein kinase family. IkappaB CC kinase subfamily. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF029684; AAC51860.1; -; mRNA. DR EMBL; AF080158; AAD08997.1; -; mRNA. DR EMBL; AF031416; AAC64675.1; -; mRNA. DR EMBL; AY663108; AAT65965.1; -; Genomic_DNA. DR EMBL; BC006231; AAH06231.1; -; mRNA. DR UniGene; Hs.656458; -. DR HSSP; P71584; 1O6Y. DR DIP; DIP:27527N; -. DR IntAct; O14920; -. DR Ensembl; ENSG00000104365; Homo sapiens. DR KEGG; hsa:3551; -. DR HGNC; HGNC:5960; IKBKB. DR HPA; CAB004447; -. DR HPA; HPA001249; -. DR MIM; 603258; gene. DR PharmGKB; PA29776; -. DR Reactome; REACT_6900.2; Immune System signaling. DR ArrayExpress; O14920; -. DR GermOnline; ENSG00000104365; Homo sapiens. DR RZPD-ProtExp; IOH6284; -. DR RZPD-ProtExp; K6125; -. DR GO; GO:0005737; C:cytoplasm; NAS:UniProtKB. DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004674; F:protein serine/threonine kinase activity; NAS:UniProtKB. DR GO; GO:0016563; F:transcriptional activator activity; NAS:UniProtKB. DR GO; GO:0051092; P:activation of NF-kappaB transcription factor; IDA:MGI. DR GO; GO:0006468; P:protein amino acid phosphorylation; NAS:UniProtKB. DR InterPro; IPR000719; Prot_kinase. DR InterPro; IPR008271; Ser_thr_pkin_AS. DR InterPro; IPR000626; Ubiquitin. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF00240; ubiquitin; 1. DR PRINTS; PR00109; TYRKINASE. DR ProDom; PD000001; Prot_kinase; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. KW Acetylation; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; KW Phosphorylation; Polymorphism; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1 756 Inhibitor of nuclear factor kappa-B FT kinase subunit beta. FT /FTId=PRO_0000086013. FT DOMAIN 15 300 Protein kinase. FT DOMAIN 458 479 Leucine-zipper (Potential). FT NP_BIND 21 29 ATP (By similarity). FT REGION 737 742 NEMO-binding. FT ACT_SITE 145 145 Proton acceptor (By similarity). FT BINDING 44 44 ATP (By similarity). FT MOD_RES 23 23 Phosphothreonine (By similarity). FT MOD_RES 177 177 Phosphoserine. FT MOD_RES 181 181 Phosphoserine. FT MOD_RES 670 670 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 672 672 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 675 675 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 682 682 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 689 689 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 692 692 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 695 695 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 697 697 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 705 705 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 733 733 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 740 740 Phosphoserine; by autocatalysis FT (Probable). FT MOD_RES 750 750 Phosphoserine; by autocatalysis FT (Probable). FT VARIANT 554 554 R -> W (in dbSNP:rs17875749). FT /FTId=VAR_021124. FT MUTAGEN 44 44 K->A: Loss of kinase activity and no FT effect on binding to NIK. FT MUTAGEN 177 177 S->A: Decrease of activity. FT MUTAGEN 177 177 S->E: Full activation. FT MUTAGEN 181 181 S->A: Decrease of activity. FT MUTAGEN 181 181 S->E: Full activation. FT CONFLICT 231 255 WHSKVRQKSEVDIVVSEDLNGTVKF -> CVRMWPGTVAHS FT CNPSTLGGRGRWI (in Ref. 6). FT CONFLICT 425 425 Q -> H (in Ref. 1). SQ SEQUENCE 756 AA; 86564 MW; F9CADF671AE9E14E CRC64; MSWSPSLTTQ TCGAWEMKER LGTGGFGNVI RWHNQETGEQ IAIKQCRQEL SPRNRERWCL EIQIMRRLTH PNVVAARDVP EGMQNLAPND LPLLAMEYCQ GGDLRKYLNQ FENCCGLREG AILTLLSDIA SALRYLHENR IIHRDLKPEN IVLQQGEQRL IHKIIDLGYA KELDQGSLCT SFVGTLQYLA PELLEQQKYT VTVDYWSFGT LAFECITGFR PFLPNWQPVQ WHSKVRQKSE VDIVVSEDLN GTVKFSSSLP YPNNLNSVLA ERLEKWLQLM LMWHPRQRGT DPTYGPNGCF KALDDILNLK LVHILNMVTG TIHTYPVTED ESLQSLKARI QQDTGIPEED QELLQEAGLA LIPDKPATQC ISDGKLNEGH TLDMDLVFLF DNSKITYETQ ISPRPQPESV SCILQEPKRN LAFFQLRKVW GQVWHSIQTL KEDCNRLQQG QRAAMMNLLR NNSCLSKMKN SMASMSQQLK AKLDFFKTSI QIDLEKYSEQ TEFGITSDKL LLAWREMEQA VELCGRENEV KLLVERMMAL QTDIVDLQRS PMGRKQGGTL DDLEEQAREL YRRLREKPRD QRTEGDSQEM VRLLLQAIQS FEKKVRVIYT QLSKTVVCKQ KALELLPKVE EVVSLMNEDE KTVVRLQEKR QKELWNLLKI ACSKVRGPVS GSPDSMNASR LSQPGQLMSQ PSTASNSLPE PAKKSEELVA EAHNLCTLLE NAIQDTVREQ DQSFTALDWS WLQTEEEEHS CLEQAS //