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E1BMN8

- NLK_BOVIN

UniProt

E1BMN8 - NLK_BOVIN

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Protein

Serine/threonine-protein kinase NLK

Gene

NLK

Organism
Bos taurus (Bovine)
Status
Reviewed - Annotation score: 4 out of 5- Protein inferred from homologyi

Functioni

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.By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Magnesium.By similarity

Enzyme regulationi

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.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei174 – 1741ATPPROSITE-ProRule annotation
Active sitei271 – 2711Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi151 – 1599ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. MAP kinase activity Source: UniProtKB-EC
  3. metal ion binding Source: UniProtKB-KW

GO - Biological processi

  1. regulation of transcription, DNA-templated Source: UniProtKB-KW
  2. transcription, DNA-templated Source: UniProtKB-KW
  3. Wnt signaling pathway Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Transcription, Transcription regulation, Wnt signaling pathway

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase NLK (EC:2.7.11.24)
Alternative name(s):
Nemo-like kinase
Gene namesi
Name:NLK
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
ProteomesiUP000009136: Unplaced

Subcellular locationi

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

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB-KW
  2. nucleus Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 534534Serine/threonine-protein kinase NLKPRO_0000413529Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei305 – 3051Phosphothreonine; by autocatalysisBy similarity
Modified residuei529 – 5291PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated on Thr-305. Intermolecular autophosphorylation on Thr-305 activates the enzyme By similarity.By similarity

Keywords - PTMi

Phosphoprotein

Interactioni

Subunit structurei

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.By similarity

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini145 – 434290Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni8 – 311304Required for interaction with TAB2By similarityAdd
BLAST
Regioni8 – 132125Sufficient for interaction with DAPK3By similarityAdd
BLAST
Regioni131 – 423293Sufficient for interaction with DAPK3By similarityAdd
BLAST
Regioni435 – 534100Required for homodimerization and kinase activation and localization to the nucleusBy similarityAdd
BLAST
Regioni441 – 53494Required for interaction with TAB2By similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi305 – 3073TQE

Domaini

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).By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

InParanoidiE1BMN8.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

E1BMN8-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MPNVFQNLVS CKRVFRELKM AAYNGGTSAA AAGHHHHHHH HLPHLPPPHL
60 70 80 90 100
HHHHHPQHHL HPGSAAAVHP VQQHTSSAAA AAAAAAAAAA MLNPGQQQPY
110 120 130 140 150
FPSPAPGQAP GPAAAAPAQV QAAAAATVKA HHHQHSHHPQ QQLDIEPDRP
160 170 180 190 200
IGYGAFGVVW SVTDPRDGKR VALKKMPNVF QNLVSCKRVF RELKMLCFFK
210 220 230 240 250
HDNVLSALDI LQPPHIDYFE EIYVVTELMQ SDLHKIIVSP QPLSSDHVKV
260 270 280 290 300
FLYQILRGLK YLHSAGILHR DIKPGNLLVN SNCVLKICDF GLARVEELDE
310 320 330 340 350
SRHMTQEVVT QYYRAPEILM GSRHYSNAID IWSVGCIFAE LLGRRILFQA
360 370 380 390 400
QSPIQQLDLI TDLLGTPSLE AMRTACEGAK AHILRGPHKQ PSLPVLYTLS
410 420 430 440 450
SQATHEAVHL LCRMLVFDPS KRISAKDALA HPYLDEGRLR YHTCMCKCCF
460 470 480 490 500
STSTGRVYTS DFEPVTNPKF DDTFEKNLSS VRQVKEIIHQ FILEQQKGNR
510 520 530
VPLCINPQSA AFKSFISSTV AQPSEMPPSP LVWE
Length:534
Mass (Da):59,339
Last modified:October 19, 2011 - v2
Checksum:i02F602E8141D57BF
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
UniGeneiBt.43996.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
UniGenei Bt.43996.

3D structure databases

ModBasei Search...
MobiDBi Search...

Chemistry

BindingDBi E1BMN8.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Phylogenomic databases

InParanoidi E1BMN8.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiNLK_BOVIN
AccessioniPrimary (citable) accession number: E1BMN8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 19, 2011
Last sequence update: October 19, 2011
Last modified: October 29, 2014
This is version 24 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3