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E1BMN8 (NLK_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 22. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
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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
OrganismBos taurus (Bovine) [Reference proteome]
Taxonomic identifier9913 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos

Protein attributes

Sequence length534 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-305. 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-305) 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-305. Intermolecular autophosphorylation on Thr-305 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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 534534Serine/threonine-protein kinase NLK
PRO_0000413529

Regions

Domain145 – 434290Protein kinase
Nucleotide binding151 – 1599ATP By similarity
Region8 – 311304Required for interaction with TAB2 By similarity
Region8 – 132125Sufficient for interaction with DAPK3 By similarity
Region131 – 423293Sufficient for interaction with DAPK3 By similarity
Region435 – 534100Required for homodimerization and kinase activation and localization to the nucleus By similarity
Region441 – 53494Required for interaction with TAB2 By similarity
Motif305 – 3073TQE

Sites

Active site2711Proton acceptor By similarity
Binding site1741ATP By similarity

Amino acid modifications

Modified residue3051Phosphothreonine; by autocatalysis By similarity
Modified residue5291Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
E1BMN8 [UniParc].

Last modified October 19, 2011. Version 2.
Checksum: 02F602E8141D57BF

FASTA53459,339
        10         20         30         40         50         60 
MPNVFQNLVS CKRVFRELKM AAYNGGTSAA AAGHHHHHHH HLPHLPPPHL HHHHHPQHHL 

        70         80         90        100        110        120 
HPGSAAAVHP VQQHTSSAAA AAAAAAAAAA MLNPGQQQPY FPSPAPGQAP GPAAAAPAQV 

       130        140        150        160        170        180 
QAAAAATVKA HHHQHSHHPQ QQLDIEPDRP IGYGAFGVVW SVTDPRDGKR VALKKMPNVF 

       190        200        210        220        230        240 
QNLVSCKRVF RELKMLCFFK HDNVLSALDI LQPPHIDYFE EIYVVTELMQ SDLHKIIVSP 

       250        260        270        280        290        300 
QPLSSDHVKV FLYQILRGLK YLHSAGILHR DIKPGNLLVN SNCVLKICDF GLARVEELDE 

       310        320        330        340        350        360 
SRHMTQEVVT QYYRAPEILM GSRHYSNAID IWSVGCIFAE LLGRRILFQA QSPIQQLDLI 

       370        380        390        400        410        420 
TDLLGTPSLE AMRTACEGAK AHILRGPHKQ PSLPVLYTLS SQATHEAVHL LCRMLVFDPS 

       430        440        450        460        470        480 
KRISAKDALA HPYLDEGRLR YHTCMCKCCF STSTGRVYTS DFEPVTNPKF DDTFEKNLSS 

       490        500        510        520        530 
VRQVKEIIHQ FILEQQKGNR VPLCINPQSA AFKSFISSTV AQPSEMPPSP LVWE 

« Hide

References

[1]"The genome sequence of taurine cattle: a window to ruminant biology and evolution."
The bovine genome sequencing and analysis consortium
Science 324:522-528(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Hereford.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AAFC03038599 Genomic DNA. No translation available.
AAFC03038600 Genomic DNA. No translation available.
AAFC03038601 Genomic DNA. No translation available.
AAFC03117551 Genomic DNA. No translation available.
AAFC03125057 Genomic DNA. No translation available.
UniGeneBt.43996.

3D structure databases

ModBaseSearch...
MobiDBSearch...

Chemistry

BindingDBE1BMN8.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

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...

Entry information

Entry nameNLK_BOVIN
AccessionPrimary (citable) accession number: E1BMN8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 19, 2011
Last sequence update: October 19, 2011
Last modified: April 16, 2014
This is version 22 of the entry and version 2 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