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E2QWQ2 (NLK_CANFA) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 25. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Serine/threonine-protein kinase NLK

EC=2.7.11.24
Alternative name(s):
Nemo-like kinase
Gene names
Name:NLK
OrganismCanis familiaris (Dog) (Canis lupus familiaris) [Reference proteome]
Taxonomic identifier9615 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis

Protein attributes

Sequence length527 AA.
Sequence statusComplete.
Protein existenceInferred from homology

General annotation (Comments)

Function

Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Activation of this pathway causes binding to and phosphorylation of the histone methyltransferase SETDB1. The NLK-SETDB1 complex subsequently interacts with PPARG, leading to methylation of PPARG target promoters at histone H3K9 and transcriptional silencing. The resulting loss of PPARG target gene transcription inhibits adipogenesis and promotes osteoblastogenesis in mesenchymal stem cells (MSCs). Negative regulator of the canonical Wnt/beta-catenin signaling pathway. Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1 By similarity.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Activated by the non-canonical Wnt signaling pathway, in which WNT5A leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298. Other cytokines such as IL6 may also activate this regulatory circuit By similarity.

Subunit structure

Homodimer. Homodimerization is required for intermolecular autophosphorylation, kinase activation and nuclear localization. Interacts with the upstream activating kinases HIPK2 and MAP3K7/TAK1. Interaction with MAP3K7/TAK1 seems to be indirect, and may be mediated by other proteins such as STAT3, TAB1 and TAB2. Interacts with and phosphorylates a number of transcription factors including FOXO1, FOXO3, FOXO4, LEF1, MYB, MYBL1, MYBL2, NOTCH1 and TCF7L2/TCF4. Interacts with DAPK3/ZIPK, and this interaction may disrupt interaction with transcription factors such as TCF7L2/TCF. Forms a complex with CHD7, PPARG and SETDB1 in response to WNT5A signaling. May interact with components of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes. Interacts with RNF138/NARF. Interacts with MEF2A By similarity.

Subcellular location

Nucleus By similarity. Cytoplasm By similarity. Note: Predominantly nuclear. A smaller fraction is cytoplasmic By similarity.

Domain

Contains a TQE activation loop motif in which autophosphorylation of the threonine residue (Thr-298) is sufficient for kinase activation. This mode of activation contrasts with that of classical MAP kinases, which contain a TXY activation loop motif in which phosphorylation of both the threonine and tyrosine residues is required for kinase activation By similarity.

Post-translational modification

Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme By similarity.

Sequence similarities

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

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
Wnt signaling pathway
   Cellular componentCytoplasm
Nucleus
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of Wnt signaling pathway

Inferred from electronic annotation. Source: Ensembl

peptidyl-threonine phosphorylation

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from electronic annotation. Source: Ensembl

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

serine phosphorylation of STAT3 protein

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

magnesium ion binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 527527Serine/threonine-protein kinase NLK
PRO_0000413530

Regions

Domain138 – 427290Protein kinase
Nucleotide binding144 – 1529ATP By similarity
Region1 – 304304Required for interaction with TAB2 By similarity
Region1 – 125125Sufficient for interaction with DAPK3 By similarity
Region124 – 416293Sufficient for interaction with DAPK3 By similarity
Region428 – 527100Required for homodimerization and kinase activation and localization to the nucleus By similarity
Region434 – 52794Required for interaction with TAB2 By similarity
Motif298 – 3003TQE
Compositional bias22 – 254Poly-Ala
Compositional bias27 – 348Poly-His
Compositional bias42 – 487Poly-His
Compositional bias71 – 8313Poly-Ala
Compositional bias106 – 1116Poly-Ala
Compositional bias115 – 1195Poly-Ala

Sites

Active site2641Proton acceptor By similarity
Binding site1671ATP By similarity

Amino acid modifications

Modified residue2981Phosphothreonine; by autocatalysis By similarity
Modified residue5221Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
E2QWQ2 [UniParc].

Last modified November 30, 2010. Version 1.
Checksum: D6D148A7D801BB19

FASTA52758,297
        10         20         30         40         50         60 
MSLCGARANA KMMAAYNGGT SAAAAGHHHH HHHHLPHLPP PHLHHHHHPQ HHLHPGSAAA 

        70         80         90        100        110        120 
VHPVQQHTSS AAAAAAAAAA AAAMLNPGQQ QPYFPSPAPG QAPGPAAAAP AQVQAAAAAT 

       130        140        150        160        170        180 
VKAHHHQHSH HPQQQLDIEP DRPIGYGAFG VVWSVTDPRD GKRVALKKMP NVFQNLVSCK 

       190        200        210        220        230        240 
RVFRELKMLC FFKHDNVLSA LDILQPPHID YFEEIYVVTE LMQSDLHKII VSPQPLSSDH 

       250        260        270        280        290        300 
VKVFLYQILR GLKYLHSAGI LHRDIKPGNL LVNSNCVLKI CDFGLARVEE LDESRHMTQE 

       310        320        330        340        350        360 
VVTQYYRAPE ILMGSRHYSN AIDIWSVGCI FAELLGRRIL FQAQSPIQQL DLITDLLGTP 

       370        380        390        400        410        420 
SLEAMRTACE GAKAHILRGP HKQPSLPVLY TLSSQATHEA VHLLCRMLVF DPSKRISAKD 

       430        440        450        460        470        480 
ALAHPYLDEG RLRYHTCMCK CCFSTSTGRV YTSDFEPITN PKFDDTFEKN LSSVRQVKEI 

       490        500        510        520 
IHQFILEQQK GNRVPLCINP QSAAFKSFIS STVAQPSEMP PSPLVWE 

« Hide

References

[1]"Genome sequence, comparative analysis and haplotype structure of the domestic dog."
Lindblad-Toh K., Wade C.M., Mikkelsen T.S., Karlsson E.K., Jaffe D.B., Kamal M., Clamp M., Chang J.L., Kulbokas E.J. III, Zody M.C., Mauceli E., Xie X., Breen M., Wayne R.K., Ostrander E.A., Ponting C.P., Galibert F., Smith D.R. expand/collapse author list , deJong P.J., Kirkness E.F., Alvarez P., Biagi T., Brockman W., Butler J., Chin C.-W., Cook A., Cuff J., Daly M.J., DeCaprio D., Gnerre S., Grabherr M., Kellis M., Kleber M., Bardeleben C., Goodstadt L., Heger A., Hitte C., Kim L., Koepfli K.-P., Parker H.G., Pollinger J.P., Searle S.M.J., Sutter N.B., Thomas R., Webber C., Baldwin J., Abebe A., Abouelleil A., Aftuck L., Ait-Zahra M., Aldredge T., Allen N., An P., Anderson S., Antoine C., Arachchi H., Aslam A., Ayotte L., Bachantsang P., Barry A., Bayul T., Benamara M., Berlin A., Bessette D., Blitshteyn B., Bloom T., Blye J., Boguslavskiy L., Bonnet C., Boukhgalter B., Brown A., Cahill P., Calixte N., Camarata J., Cheshatsang Y., Chu J., Citroen M., Collymore A., Cooke P., Dawoe T., Daza R., Decktor K., DeGray S., Dhargay N., Dooley K., Dooley K., Dorje P., Dorjee K., Dorris L., Duffey N., Dupes A., Egbiremolen O., Elong R., Falk J., Farina A., Faro S., Ferguson D., Ferreira P., Fisher S., FitzGerald M., Foley K., Foley C., Franke A., Friedrich D., Gage D., Garber M., Gearin G., Giannoukos G., Goode T., Goyette A., Graham J., Grandbois E., Gyaltsen K., Hafez N., Hagopian D., Hagos B., Hall J., Healy C., Hegarty R., Honan T., Horn A., Houde N., Hughes L., Hunnicutt L., Husby M., Jester B., Jones C., Kamat A., Kanga B., Kells C., Khazanovich D., Kieu A.C., Kisner P., Kumar M., Lance K., Landers T., Lara M., Lee W., Leger J.-P., Lennon N., Leuper L., LeVine S., Liu J., Liu X., Lokyitsang Y., Lokyitsang T., Lui A., Macdonald J., Major J., Marabella R., Maru K., Matthews C., McDonough S., Mehta T., Meldrim J., Melnikov A., Meneus L., Mihalev A., Mihova T., Miller K., Mittelman R., Mlenga V., Mulrain L., Munson G., Navidi A., Naylor J., Nguyen T., Nguyen N., Nguyen C., Nguyen T., Nicol R., Norbu N., Norbu C., Novod N., Nyima T., Olandt P., O'Neill B., O'Neill K., Osman S., Oyono L., Patti C., Perrin D., Phunkhang P., Pierre F., Priest M., Rachupka A., Raghuraman S., Rameau R., Ray V., Raymond C., Rege F., Rise C., Rogers J., Rogov P., Sahalie J., Settipalli S., Sharpe T., Shea T., Sheehan M., Sherpa N., Shi J., Shih D., Sloan J., Smith C., Sparrow T., Stalker J., Stange-Thomann N., Stavropoulos S., Stone C., Stone S., Sykes S., Tchuinga P., Tenzing P., Tesfaye S., Thoulutsang D., Thoulutsang Y., Topham K., Topping I., Tsamla T., Vassiliev H., Venkataraman V., Vo A., Wangchuk T., Wangdi T., Weiand M., Wilkinson J., Wilson A., Yadav S., Yang S., Yang X., Young G., Yu Q., Zainoun J., Zembek L., Zimmer A., Lander E.S.
Nature 438:803-819(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Boxer.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AAEX02035279 Genomic DNA. No translation available.
RefSeqXP_868108.2. XM_863015.3.

3D structure databases

ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSCAFT00000029610; ENSCAFP00000027521; ENSCAFG00000018650.
GeneID491160.
KEGGcfa:491160.

Organism-specific databases

CTD51701.

Phylogenomic databases

GeneTreeENSGT00730000110881.
KOK04468.
OMACKCCYTT.
OrthoDBEOG72RMZ3.
TreeFamTF315210.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio20864043.

Entry information

Entry nameNLK_CANFA
AccessionPrimary (citable) accession number: E2QWQ2
Entry history
Integrated into UniProtKB/Swiss-Prot: October 19, 2011
Last sequence update: November 30, 2010
Last modified: March 19, 2014
This is version 25 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families