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Q60680 (IKKA_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 121. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Inhibitor of nuclear factor kappa-B kinase subunit alpha
Short name=I-kappa-B kinase alpha
Short name=IKK-A
Short name=IKK-alpha
Short name=IkBKA
Short name=IkappaB kinase
EC=2.7.11.10
Alternative name(s):
Conserved helix-loop-helix ubiquitous kinase
I-kappa-B kinase 1
Short name=IKK1
Nuclear factor NF-kappa-B inhibitor kinase alpha
Short name=NFKBIKA
Gene names
Name:Chuk
Synonyms:Ikka
OrganismMus musculus (Mouse)
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length745 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.11

Catalytic activity

ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].

Enzyme regulation

Activated when phosphorylated and inactivated when dephosphorylated.

Subunit structure

Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, IKBKAP and MAP3K14. Directly interacts with IKK-gamma/NEMO and TRPC4AP. May interact with TRAF2. Interacts with NALP2. May interact with MAVS/IPS1. Interacts with ARRB1 By similarity. Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity By similarity. Interacts with PIAS1; this interaction induces PIAS1 phosphorylation By similarity. Interacts with ARRB2. Ref.12 Ref.13

Subcellular location

Cytoplasm. Nucleus. Note: Shuttles between the cytoplasm and the nucleus. Ref.11

Tissue specificity

Ubiquitous only for isoform 1, isoforms 2 and 3 are expressed predominantly in brain and T-lymphocytes.

Developmental stage

Maximally expressed at E7 day followed by E11, E15 and E17 days. In the limb development, its expression predominates in the limb buds at E12.5 day.

Domain

The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.

Post-translational modification

Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated. Ref.7 Ref.9

Disruption phenotype

Mice show abnormal appearance and die within 4 hours after birth. The epidermal cells are highly proliferative with dysregulated epidermal differentiation. Ref.5

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological processI-kappaB phosphorylation

Traceable author statement. Source: MGI

lactation

Inferred from mutant phenotype. Source: MGI

mammary gland alveolus development

Inferred from mutant phenotype. Source: MGI

mammary gland epithelial cell proliferation

Inferred from mutant phenotype. Source: MGI

morphogenesis of an epithelial sheet

Inferred from mutant phenotype. Source: MGI

odontogenesis of dentin-containing tooth

Inferred from mutant phenotype. Source: MGI

osteoclast differentiation

Inferred from mutant phenotype. Source: MGI

positive regulation of I-kappaB kinase/NF-kappaB cascade

Inferred from mutant phenotype. Source: MGI

   Cellular componentCD40 receptor complex

Inferred from direct assay. Source: BHF-UCL

cytoplasm

Traceable author statement. Source: MGI

internal side of plasma membrane

Inferred from direct assay. Source: BHF-UCL

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

IkappaB kinase activity

Inferred from electronic annotation. Source: EC

protein binding

Inferred from physical interaction Ref.13. Source: UniProtKB

receptor signaling protein serine/threonine kinase activity

Traceable author statement. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Fam92a1Q8BP224EBI-646260,EBI-646638
IkbkgO885223EBI-646245,EBI-998011
Irf7P704343EBI-646245,EBI-997907
Krt10P025356EBI-646260,EBI-646288
MAP3K14Q995583EBI-646264,EBI-358011From a different organism.
NFKBIAP259632EBI-646264,EBI-307386From a different organism.
Pde4dipB7ZNY04EBI-646260,EBI-659248

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q60680-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q60680-2)

Also known as: Delta LH;

The sequence of this isoform differs from the canonical sequence as follows:
     452-471: MLSLLRYNANLTKMKNTLIS → IFRKNVKSMERNGRKGHSLF
     472-745: Missing.
Isoform 3 (identifier: Q60680-3)

Also known as: Delta H;

The sequence of this isoform differs from the canonical sequence as follows:
     577-584: DHLYSDST → GKTLQSQY
     585-745: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 745745Inhibitor of nuclear factor kappa-B kinase subunit alpha
PRO_0000086012

Regions

Domain15 – 300286Protein kinase
Domain455 – 47622Leucine-zipper
Nucleotide binding21 – 299ATP By similarity
Region738 – 7436NEMO-binding

Sites

Active site1441Proton acceptor By similarity
Binding site441ATP By similarity

Amino acid modifications

Modified residue231Phosphothreonine; by PKB/AKT1 and SGK1 By similarity
Modified residue1761Phosphoserine; by MAP3K14 By similarity
Modified residue1801Phosphoserine; by SGK1 By similarity

Natural variations

Alternative sequence452 – 47120MLSLL…NTLIS → IFRKNVKSMERNGRKGHSLF in isoform 2.
VSP_004866
Alternative sequence472 – 745274Missing in isoform 2.
VSP_004867
Alternative sequence577 – 5848DHLYSDST → GKTLQSQY in isoform 3.
VSP_004868
Alternative sequence585 – 745161Missing in isoform 3.
VSP_004869

Experimental info

Sequence conflict2361K → E in BAB31335. Ref.3
Sequence conflict4001S → Y in BAB31335. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 3FEF5582AFF92233

FASTA74584,729
        10         20         30         40         50         60 
MERPPGLRPG AGGPWEMRER LGTGGFGNVS LYQHRELDLK IAIKSCRLEL SSKNRERWCH 

        70         80         90        100        110        120 
EIQIMKKLDH ANVVKACDVP EELNFLINDV PLLAMEYCSG GDLRKLLNKP ENCCGLKESQ 

       130        140        150        160        170        180 
ILSLLSDIGS GIRYLHENKI IHRDLKPENI VLQDVGGKTI HKIIDLGYAK DVDQGSLCTS 

       190        200        210        220        230        240 
FVGTLQYLAP ELFENKPYTA TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK 

       250        260        270        280        290        300 
CIFACEEMTG EVRFSSHLPQ PNSLCSLIVE PMESWLQLML NWDPQQRGGP IDLTLKQPRC 

       310        320        330        340        350        360 
FALMDHILNL KIVHILNMTS AKIISFLLPC DESLHSLQSR IERETGINTG SQELLSETGI 

       370        380        390        400        410        420 
SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS RSLSDCVNYI VQDSKIQLPI 

       430        440        450        460        470        480 
IQLRKVWAEA VHYVSGLKED YSRLFQGQRA AMLSLLRYNA NLTKMKNTLI SASQQLKAKL 

       490        500        510        520        530        540 
EFFRKSIQLD LERYSEQMTY GISSEKMLKA WKEMEEKAIH YSEVGVIGYL EDQIMSLHTE 

       550        560        570        580        590        600 
IMELQKSPYG RRQGDLMESL EQRAIDLYKQ LKHRPPDHLY SDSTEMVKII VHTVQSQDRV 

       610        620        630        640        650        660 
LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI WHLLKIACTQ 

       670        680        690        700        710        720 
SSARSLVGSS LEGTVTPPVS AWLPPTLADR EHPLTCVVTP QDGETLAQMI EENLNCLGHL 

       730        740 
STIIREANED QSSSLMSLDW SWLAE

« Hide

Isoform 2 (Delta LH) [UniParc].

Checksum: 14F1EFF71B4A17EE
Show »

FASTA47153,544
Isoform 3 (Delta H) [UniParc].

Checksum: D99BB8A6DF1CA4EB
Show »

FASTA58466,805

References

« Hide 'large scale' references
[1]"CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19."
Mock B.A., Connelly M.A., McBride O.W., Kozak C.A., Marcu K.B.
Genomics 27:348-351(1995) [PubMed: 7558004] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Strain: BALB/c.
[2]"CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain."
Connelly M.A., Marcu K.B.
Cell. Mol. Biol. Res. 41:537-549(1995) [PubMed: 8777433] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Strain: BALB/c.
[3]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Strain: C57BL/6J.
Tissue: Colon.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Eye.
[5]"Limb and skin abnormalities in mice lacking IKKalpha."
Takeda K., Takeuchi O., Tsujimura T., Itami S., Adachi O., Kawai T., Sanjo H., Yoshikawa K., Terada N., Akira S.
Science 284:313-316(1999) [PubMed: 10195895] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[6]"Functional isoforms of IkappaB kinase alpha (IKKalpha) lacking leucine zipper and helix-loop-helix domains reveal that IKKalpha and IKKbeta have different activation requirements."
McKenzie F.R., Connelly M.A., Balzarano D., Mueller J.R., Geleziunas R., Marcu K.B.
Mol. Cell. Biol. 20:2635-2649(2000) [PubMed: 10733566] [Abstract]
Cited for: ALTERNATIVE SPLICING.
[7]"Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1."
Nakano H., Shindo M., Sakon S., Nishinaka S., Mihara M., Yagita H., Okumura K.
Proc. Natl. Acad. Sci. U.S.A. 95:3537-3542(1998) [PubMed: 9520401] [Abstract]
Cited for: PHOSPHORYLATION BY MAP3K14/NIK.
[8]"Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation."
Delhase M., Hayakawa M., Chen Y., Karin M.
Science 284:309-313(1999) [PubMed: 10195894] [Abstract]
Cited for: IKKA-IKKB BINDING.
[9]"Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase."
Nemoto S., DiDonato J.A., Lin A.
Mol. Cell. Biol. 18:7336-7343(1998) [PubMed: 9819420] [Abstract]
Cited for: IKK PHOSPHORYLATION.
[10]"The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection."
Jobin C., Sartor R.B.
Am. J. Physiol. 278:C451-C462(2000) [PubMed: 10712233] [Abstract]
Cited for: REVIEW.
[11]"Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression."
Yamamoto Y., Verma U.N., Prajapati S., Kwak Y.T., Gaynor R.B.
Nature 423:655-659(2003) [PubMed: 12789342] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[12]"Beta2-adrenergic receptor regulates Toll-like receptor-4-induced nuclear factor-kappaB activation through beta-arrestin 2."
Kizaki T., Izawa T., Sakurai T., Haga S., Taniguchi N., Tajiri H., Watanabe K., Day N.K., Toba K., Ohno H.
Immunology 124:348-356(2008) [PubMed: 18194271] [Abstract]
Cited for: INTERACTION WITH ARRB2.
[13]"Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression."
Teo H., Ghosh S., Luesch H., Ghosh A., Wong E.T., Malik N., Orth A., de Jesus P., Perry A.S., Oliver J.D., Tran N.L., Speiser L.J., Wong M., Saez E., Schultz P., Chanda S.K., Verma I.M., Tergaonkar V.
Nat. Cell Biol. 12:758-767(2010) [PubMed: 20622870] [Abstract]
Cited for: INTERACTION WITH TERF2IP.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		U12473 mRNA. Translation: AAC52589.1.
AK018671 mRNA. Translation: BAB31335.1.
BC018243 mRNA. Translation: AAH18243.1.
IPIIPI00119213.
IPI00230069.
IPI00400114.
PIRI49101.
UniGeneMm.3996.

3D structure databases

ProteinModelPortalQ60680.
SMRQ60680. Positions 16-660, 703-744.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-29719N.
IntActQ60680. 27 interactions.
MINTMINT-267529.
STRINGQ60680.

PTM databases

PhosphoSiteQ60680.

Proteomic databases

PRIDEQ60680.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000112015; ENSMUSP00000107646; ENSMUSG00000025199.
UCSCuc008hpi.2. mouse.

Organism-specific databases

MGIMGI:99484. Chuk.

Phylogenomic databases

GeneTreeENSGT00530000063051.
HOGENOMHBG358635.
HOVERGENHBG018241.
InParanoidQ60680.
OrthoDBEOG4SJ5D7.

Enzyme and pathway databases

BRENDA2.7.11.10. 3474.

Gene expression databases

ArrayExpressQ60680.
BgeeQ60680.
CleanExMM_CHUK.
GenevestigatorQ60680.
GermOnlineENSMUSG00000025199. Mus musculus.

Family and domain databases

InterProIPR022007. IKKbetaNEMObind.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF12179. IKKbetaNEMObind. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF56112. Kinase_like. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio281918.
SOURCESearch...

Entry information

Entry nameIKKA_MOUSE
AccessionPrimary (citable) accession number: Q60680
Secondary accession number(s): Q80VU2, Q9D2X3
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: November 1, 1996
Last modified: January 25, 2012
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents