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Q99558 (M3K14_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 14

EC=2.7.11.25
Alternative name(s):
NF-kappa-beta-inducing kinase
Short name=HsNIK
Serine/threonine-protein kinase NIK
Gene names
Name:MAP3K14
Synonyms:NIK
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length947 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner. Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Subunit structure

Interacts with TRAF2, TRAF5, TRAF6, IKKA and NFKB2/P100 By similarity. Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.15

Subcellular location

Cytoplasm.

Tissue specificity

Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon. Ref.1

Post-translational modification

Autophosphorylated. Phosphorylation at Thr-559 is required to activates its kinase activity and 'Lys-63'-linked polyubiquitination. Phosphorylated by CHUK/IKKA leading to MAP3K14 destabilization. Ref.11 Ref.15

Ubiquitinated. Undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. 'Lys-48'-linked polyubiquitination leads to its degradation by the proteasome, while 'Lys-63'-linked polyubiquitination stabilizes and activates it. Ref.8 Ref.15

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 947947Mitogen-activated protein kinase kinase kinase 14
PRO_0000086266

Regions

Domain400 – 655256Protein kinase
Nucleotide binding406 – 4149ATP By similarity
Region401 – 653253Interaction with ZFP91

Sites

Active site5151Proton acceptor By similarity
Binding site4291ATP By similarity

Amino acid modifications

Modified residue5591Phosphothreonine Ref.15

Natural variations

Natural variant1401S → N. Ref.14
Corresponds to variant rs11574819 [ dbSNP | Ensembl ].
VAR_040711
Natural variant2551T → M.
Corresponds to variant rs11574820 [ dbSNP | Ensembl ].
VAR_051641
Natural variant5141G → K in a lung neuroendocrine carcinoma sample; somatic mutation; requires 2 nucleotide substitutions. Ref.14
VAR_040712
Natural variant6741H → Y.
Corresponds to variant rs11867907 [ dbSNP | Ensembl ].
VAR_051642
Natural variant7641T → A. Ref.14
Corresponds to variant rs56302559 [ dbSNP | Ensembl ].
VAR_040713
Natural variant8521T → I in an ovarian mucinous carcinoma sample; somatic mutation. Ref.14
VAR_040714
Natural variant9281P → H. Ref.14
Corresponds to variant rs56036201 [ dbSNP | Ensembl ].
VAR_040715

Experimental info

Mutagenesis429 – 4302KK → AA: Loss of autophosphorylation and 'Lys-63'-linked ubiquitination. Ref.1
Mutagenesis5591T → A: Abolishes 'Lys-63'-linked ubiquitination. Ref.1 Ref.15
Sequence conflict251A → P in CAA71306. Ref.1
Sequence conflict3481G → S in CAA71306. Ref.1
Sequence conflict8801R → G in BAF82892. Ref.2

Secondary structure

............................................................ 947
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99558 [UniParc].

Last modified April 4, 2006. Version 2.
Checksum: C9D10F67FF7F48AC

FASTA947104,042
        10         20         30         40         50         60 
MAVMEMACPG APGSAVGQQK ELPKAKEKTP PLGKKQSSVY KLEAVEKSPV FCGKWEILND 

        70         80         90        100        110        120 
VITKGTAKEG SEAGPAAISI IAQAECENSQ EFSPTFSERI FIAGSKQYSQ SESLDQIPNN 

       130        140        150        160        170        180 
VAHATEGKMA RVCWKGKRRS KARKKRKKKS SKSLAHAGVA LAKPLPRTPE QESCTIPVQE 

       190        200        210        220        230        240 
DESPLGAPYV RNTPQFTKPL KEPGLGQLCF KQLGEGLRPA LPRSELHKLI SPLQCLNHVW 

       250        260        270        280        290        300 
KLHHPQDGGP LPLPTHPFPY SRLPHPFPFH PLQPWKPHPL ESFLGKLACV DSQKPLPDPH 

       310        320        330        340        350        360 
LSKLACVDSP KPLPGPHLEP SCLSRGAHEK FSVEEYLVHA LQGSVSSGQA HSLTSLAKTW 

       370        380        390        400        410        420 
AARGSRSREP SPKTEDNEGV LLTEKLKPVD YEYREEVHWA THQLRLGRGS FGEVHRMEDK 

       430        440        450        460        470        480 
QTGFQCAVKK VRLEVFRAEE LMACAGLTSP RIVPLYGAVR EGPWVNIFME LLEGGSLGQL 

       490        500        510        520        530        540 
VKEQGCLPED RALYYLGQAL EGLEYLHSRR ILHGDVKADN VLLSSDGSHA ALCDFGHAVC 

       550        560        570        580        590        600 
LQPDGLGKSL LTGDYIPGTE THMAPEVVLG RSCDAKVDVW SSCCMMLHML NGCHPWTQFF 

       610        620        630        640        650        660 
RGPLCLKIAS EPPPVREIPP SCAPLTAQAI QEGLRKEPIH RVSAAELGGK VNRALQQVGG 

       670        680        690        700        710        720 
LKSPWRGEYK EPRHPPPNQA NYHQTLHAQP RELSPRAPGP RPAEETTGRA PKLQPPLPPE 

       730        740        750        760        770        780 
PPEPNKSPPL TLSKEESGMW EPLPLSSLEP APARNPSSPE RKATVPEQEL QQLEIELFLN 

       790        800        810        820        830        840 
SLSQPFSLEE QEQILSCLSI DSLSLSDDSE KNPSKASQSS RDTLSSGVHS WSSQAEARSS 

       850        860        870        880        890        900 
SWNMVLARGR PTDTPSYFNG VKVQIQSLNG EHLHIREFHR VKVGDIATGI SSQIPAAAFS 

       910        920        930        940 
LVTKDGQPVR YDMEVPDSGI DLQCTLAPDG SFAWSWRVKH GQLENRP 

« Hide

References

« Hide 'large scale' references
[1]"MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1."
Malinin N.L., Boldin M.P., Kovalenko A.V., Wallach D.
Nature 385:540-544(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 429-LYS-LYS-430, TISSUE SPECIFICITY.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Thalamus.
[3]NHLBI resequencing and genotyping service (RS&G)
Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lymph.
[6]"Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein."
Jensen L.E., Whitehead A.S.
J. Immunol. 171:1500-1506(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PELI3.
[7]"NIK is a component of the EGF/heregulin receptor signaling complexes."
Chen D., Xu L.G., Chen L., Li L., Zhai Z., Shu H.B.
Oncogene 22:4348-4355(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GRB10.
[8]"Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation."
Liao G., Zhang M., Harhaj E.W., Sun S.C.
J. Biol. Chem. 279:26243-26250(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, UBIQUITINATION, INTERACTION WITH TRAF3.
[9]"beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha."
Witherow D.S., Garrison T.R., Miller W.E., Lefkowitz R.J.
Proc. Natl. Acad. Sci. U.S.A. 101:8603-8607(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB1 AND ARRB2.
[10]"NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation."
Hu W.-H., Pendergast J.S., Mo X.-M., Brambilla R., Bracchi-Ricard V., Li F., Walters W.M., Blits B., He L., Schaal S.M., Bethea J.R.
J. Biol. Chem. 280:29233-29241(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NIBP.
[11]"Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation."
Razani B., Zarnegar B., Ytterberg A.J., Shiba T., Dempsey P.W., Ware C.F., Loo J.A., Cheng G.
Sci. Signal. 3:RA41-RA41(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CHUK/IKKA.
[12]"Structure of the nuclear factor kappaB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation."
Liu J., Sudom A., Min X., Cao Z., Gao X., Ayres M., Lee F., Cao P., Johnstone S., Plotnikova O., Walker N., Chen G., Wang Z.
J. Biol. Chem. 287:27326-27334(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 330-680.
[13]"The crystal structure of the catalytic domain of the NF-kappaB inducing kinase reveals a narrow but flexible active site."
de Leon-Boenig G., Bowman K.K., Feng J.A., Crawford T., Everett C., Franke Y., Oh A., Stanley M., Staben S.T., Starovasnik M.A., Wallweber H.J., Wu J., Wu L.C., Johnson A.R., Hymowitz S.G.
Structure 20:1704-1714(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 308-673.
[14]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-140; LYS-514; ALA-764; ILE-852 AND HIS-928.
[15]"An atypical E3 ligase zinc finger protein 91 stabilizes and activates NF-kappaB-inducing kinase via Lys63-linked ubiquitination."
Jin X., Jin H.R., Jung H.S., Lee S.J., Lee J.H., Lee J.J.
J. Biol. Chem. 285:30539-30547(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-559, UBIQUITINATION, INTERACTION WITH ZFP91, MUTAGENESIS OF 429-LYS-LYS-430 AND THR-559.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Y10256 mRNA. Translation: CAA71306.1.
AK290203 mRNA. Translation: BAF82892.1.
DQ314874 Genomic DNA. Translation: ABC40733.1.
CH471178 Genomic DNA. Translation: EAW51529.1.
CH471178 Genomic DNA. Translation: EAW51530.1.
BC035576 mRNA. Translation: AAH35576.1.
RefSeqNP_003945.2. NM_003954.4.
UniGeneHs.404183.
Hs.735695.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4DN5X-ray2.50A/B330-680[»]
4G3DX-ray2.90A/B/D/E308-673[»]
4IDTX-ray2.40A/B330-680[»]
4IDVX-ray2.90A/B/C/D330-680[»]
ProteinModelPortalQ99558.
SMRQ99558. Positions 333-675.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114487. 32 interactions.
DIPDIP-27522N.
IntActQ99558. 27 interactions.
MINTMINT-88636.
STRING9606.ENSP00000342059.

Chemistry

BindingDBQ99558.
ChEMBLCHEMBL5888.
GuidetoPHARMACOLOGY2074.

PTM databases

PhosphoSiteQ99558.

Polymorphism databases

DMDM92090612.

Proteomic databases

PaxDbQ99558.
PRIDEQ99558.

Protocols and materials databases

DNASU9020.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID9020.
KEGGhsa:9020.
UCSCuc002iiv.1. human.

Organism-specific databases

CTD9020.
GeneCardsGC17M043466.
HGNCHGNC:6853. MAP3K14.
MIM604655. gene.
neXtProtNX_Q99558.
PharmGKBPA30597.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000113436.
HOVERGENHBG052384.
InParanoidQ99558.
KOK04466.
PhylomeDBQ99558.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.
SignaLinkQ99558.

Gene expression databases

CleanExHS_MAP3K14.
GenevestigatorQ99558.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR017425. MAPKKK14.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF038175. MAPKKK14. 1 hit.
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAP3K14. human.
GeneWikiMAP3K14.
GenomeRNAi9020.
NextBio33793.
PROQ99558.
SOURCESearch...

Entry information

Entry nameM3K14_HUMAN
AccessionPrimary (citable) accession number: Q99558
Secondary accession number(s): A8K2D8, D3DX67, Q8IYN1
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: April 4, 2006
Last modified: April 16, 2014
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM