Q99558 (M3K14_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	947 AA.
Sequence status	Complete.
Protein existence	Evidence 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.13
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.13 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.13
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB kinase/NF-kappaB cascade Inferred from sequence or structural similarity. Source: UniProtKB MAPK cascade Inferred from electronic annotation. Source: GOC T cell costimulation Traceable author statement. Source: Reactome activation of MAPKK activity Inferred from electronic annotation. Source: GOC cellular response to mechanical stimulus Inferred from expression pattern PubMed 19593445. Source: UniProtKB immune response Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype PubMed 10094049. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay. Source: HPA
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Inferred from electronic annotation. Source: EC NF-kappaB-inducing kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CHUK	O15111	4	EBI-358011,EBI-81249
Chuk	Q60680-2	3	EBI-358011,EBI-646264	From a different organism.
IKBKB	O14920	2	EBI-358011,EBI-81266

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 947

947

Mitogen-activated protein kinase kinase kinase 14

PRO_0000086266

Regions

Domain

400 – 655

256

Protein kinase

Nucleotide binding

406 – 414

9

ATP By similarity

Region

401 – 653

253

Interaction with ZFP91

Sites

Active site

515

1

Proton acceptor By similarity

Binding site

429

1

ATP By similarity

Amino acid modifications

Modified residue

559

1

Phosphothreonine Ref.13

Natural variations

Natural variant

140

1

S → N. Ref.12
Corresponds to variant rs11574819 [ dbSNP | Ensembl ].

VAR_040711

Natural variant

255

1

T → M.
Corresponds to variant rs11574820 [ dbSNP | Ensembl ].

VAR_051641

Natural variant

514

1

G → K in a lung neuroendocrine carcinoma sample; somatic mutation; requires 2 nucleotide substitutions. Ref.12

VAR_040712

Natural variant

674

1

H → Y.
Corresponds to variant rs11867907 [ dbSNP | Ensembl ].

VAR_051642

Natural variant

764

1

T → A. Ref.12
Corresponds to variant rs56302559 [ dbSNP | Ensembl ].

VAR_040713

Natural variant

852

1

T → I in an ovarian mucinous carcinoma sample; somatic mutation. Ref.12

VAR_040714

Natural variant

928

1

P → H. Ref.12
Corresponds to variant rs56036201 [ dbSNP | Ensembl ].

VAR_040715

Experimental info

Mutagenesis

429 – 430

2

KK → AA: Loss of autophosphorylation and 'Lys-63'-linked ubiquitination. Ref.1

Mutagenesis

559

1

T → A: Abolishes 'Lys-63'-linked ubiquitination. Ref.1 Ref.13

Sequence conflict

25

1

A → P in CAA71306. Ref.1

Sequence conflict

348

1

G → S in CAA71306. Ref.1

Sequence conflict

880

1

R → G in BAF82892. Ref.2

Secondary structure

1

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947

Helix Strand Turn

Details...

Helix

334 – 341

8

Beta strand

345 – 347

3

Helix

350 – 363

14

Beta strand

377 – 381

5

Turn

395 – 397

3

Beta strand

398 – 401

4

Beta strand

406 – 408

3

Beta strand

413 – 419

7

Turn

420 – 422

3

Beta strand

425 – 432

8

Turn

433 – 435

3

Helix

439 – 442

4

Turn

443 – 446

4

Beta strand

455 – 461

7

Beta strand

464 – 469

6

Helix

477 – 484

8

Helix

489 – 508

20

Helix

518 – 520

3

Beta strand

521 – 523

3

Beta strand

530 – 532

3

Beta strand

543 – 547

5

Turn

550 – 553

4

Helix

560 – 562

3

Helix

565 – 568

4

Helix

576 – 591

16

Turn

595 – 599

5

Helix

605 – 610

6

Helix

614 – 617

4

Helix

624 – 633

10

Turn

638 – 640

3

Helix

644 – 658

15

Sequences

	Sequence		Length	Mass (Da)
	Q99558 [UniParc]. Last modified April 4, 2006. Version 2. Checksum: C9D10F67FF7F48AC	FASTA	947	104,042
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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]	"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. , 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.
[13]	"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.

IPI

IPI00016099.

RefSeq

NP_003945.2. NM_003954.3.

UniGene

Hs.404183.
Hs.735695.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4DN5	X-ray	2.50	A/B	330-680	[»]
4G3D	X-ray	2.90	A/B/D/E	308-673	[»]

ProteinModelPortal

Q99558.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-27522N.

IntAct

Q99558. 13 interactions.

MINT

MINT-88636.

STRING

9606.ENSP00000342059.

PTM databases

PhosphoSite

Q99558.

Polymorphism databases

DMDM

92090612.

Proteomic databases

PaxDb

Q99558.

PRIDE

Q99558.

Protocols and materials databases

DNASU

9020.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

9020.

KEGG

hsa:9020.

UCSC

uc002iiv.1. human.

Organism-specific databases

CTD

9020.

GeneCards

GC17M043370.

HGNC

HGNC:6853. MAP3K14.

MIM

604655. gene.

neXtProt

NX_Q99558.

PharmGKB

PA30597.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000113436.

HOVERGEN

HBG052384.

InParanoid

Q99558.

KO

K04466.

OrthoDB

EOG44MXRB.

Enzyme and pathway databases

Pathway_Interaction_DB

nfkappabalternativepathway. Alternative NF-kappaB pathway.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
avb3_opn_pathway. Osteopontin-mediated events.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.

Reactome

REACT_6900. Immune System.

Gene expression databases

CleanEx

HS_MAP3K14.

Genevestigator

Q99558.

GermOnline

ENSG00000006062. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR017425. MAPKKK14.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PIRSF

PIRSF038175. MAPKKK14. 1 hit.

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q99558.

ChEMBL

CHEMBL5888.

ChiTaRS

MAP3K14. human.

GenomeRNAi

9020.

NextBio

33793.

SOURCE

Search...

Entry information

Entry name

M3K14_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 132 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.