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Protein

Serine/threonine-protein kinase NLK

Gene

NLK

Organism
Canis lupus familiaris (Dog) (Canis familiaris)
Status
Reviewed-Annotation score: Annotation score: 5 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. Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner.By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+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-298. Other cytokines such as IL6 may also activate this regulatory circuit (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei167ATPPROSITE-ProRule annotation1
Active sitei264Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi144 – 152ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

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

Enzyme and pathway databases

ReactomeiR-CFA-4086398. Ca2+ pathway.

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
OrganismiCanis lupus familiaris (Dog) (Canis familiaris)
Taxonomic identifieri9615 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis
Proteomesi
  • UP000002254 Componenti: Chromosome 9

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity

  • Note: Predominantly nuclear. A smaller fraction is cytoplasmic (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00004135301 – 527Serine/threonine-protein kinase NLKAdd BLAST527

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei298Phosphothreonine; by autocatalysisBy similarity1
Modified residuei522PhosphoserineBy similarity1

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiE2QWQ2.

Interactioni

Subunit structurei

Homodimer. Homodimerization is required for intermolecular autophosphorylation, kinase activation and nuclear localization (By similarity). May interact with components of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes (By similarity). Interacts with LEF1, MEF2A, MYBL1 and MYBL2 (By similarity). 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, MYB, NOTCH1 and TCF7L2/TCF4. Interacts with DAPK3/ZIPK, and this interaction may disrupt interaction with transcription factors such as TCF7L2/TCF4. Forms a transcriptional repressor complex with CHD7, PPARG and SETDB1. Interacts with RNF138/NARF (By similarity). Interacts with ATF5; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner (By similarity).By similarity

Protein-protein interaction databases

STRINGi9615.ENSCAFP00000027521.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini138 – 427Protein kinasePROSITE-ProRule annotationAdd BLAST290

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 304Required for interaction with TAB2By similarityAdd BLAST304
Regioni1 – 125Sufficient for interaction with DAPK3By similarityAdd BLAST125
Regioni124 – 416Sufficient for interaction with DAPK3By similarityAdd BLAST293
Regioni428 – 527Required for homodimerization and kinase activation and localization to the nucleusBy similarityAdd BLAST100
Regioni434 – 527Required for interaction with TAB2By similarityAdd BLAST94

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi298 – 300TQE3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi22 – 25Poly-Ala4
Compositional biasi27 – 34Poly-His8
Compositional biasi42 – 48Poly-His7
Compositional biasi71 – 83Poly-AlaAdd BLAST13
Compositional biasi106 – 111Poly-Ala6
Compositional biasi115 – 119Poly-Ala5

Domaini

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).By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0664. Eukaryota.
ENOG410XRAQ. LUCA.
GeneTreeiENSGT00550000074298.
InParanoidiE2QWQ2.
KOiK04468.
OMAiDDGFEKN.
OrthoDBiEOG091G05X6.
TreeFamiTF315210.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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.

E2QWQ2-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSLCGARANA KMMAAYNGGT SAAAAGHHHH HHHHLPHLPP PHLHHHHHPQ
60 70 80 90 100
HHLHPGSAAA VHPVQQHTSS AAAAAAAAAA AAAMLNPGQQ QPYFPSPAPG
110 120 130 140 150
QAPGPAAAAP AQVQAAAAAT VKAHHHQHSH HPQQQLDIEP DRPIGYGAFG
160 170 180 190 200
VVWSVTDPRD GKRVALKKMP NVFQNLVSCK RVFRELKMLC FFKHDNVLSA
210 220 230 240 250
LDILQPPHID YFEEIYVVTE LMQSDLHKII VSPQPLSSDH VKVFLYQILR
260 270 280 290 300
GLKYLHSAGI LHRDIKPGNL LVNSNCVLKI CDFGLARVEE LDESRHMTQE
310 320 330 340 350
VVTQYYRAPE ILMGSRHYSN AIDIWSVGCI FAELLGRRIL FQAQSPIQQL
360 370 380 390 400
DLITDLLGTP SLEAMRTACE GAKAHILRGP HKQPSLPVLY TLSSQATHEA
410 420 430 440 450
VHLLCRMLVF DPSKRISAKD ALAHPYLDEG RLRYHTCMCK CCFSTSTGRV
460 470 480 490 500
YTSDFEPITN PKFDDTFEKN LSSVRQVKEI IHQFILEQQK GNRVPLCINP
510 520
QSAAFKSFIS STVAQPSEMP PSPLVWE
Length:527
Mass (Da):58,297
Last modified:November 30, 2010 - v1
Checksum:iD6D148A7D801BB19
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AAEX02035279 Genomic DNA. No translation available.
RefSeqiXP_868108.2. XM_863015.4.

Genome annotation databases

EnsembliENSCAFT00000029610; ENSCAFP00000027521; ENSCAFG00000018650.
GeneIDi491160.
KEGGicfa:491160.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AAEX02035279 Genomic DNA. No translation available.
RefSeqiXP_868108.2. XM_863015.4.

3D structure databases

ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9615.ENSCAFP00000027521.

Proteomic databases

PaxDbiE2QWQ2.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSCAFT00000029610; ENSCAFP00000027521; ENSCAFG00000018650.
GeneIDi491160.
KEGGicfa:491160.

Organism-specific databases

CTDi51701.

Phylogenomic databases

eggNOGiKOG0664. Eukaryota.
ENOG410XRAQ. LUCA.
GeneTreeiENSGT00550000074298.
InParanoidiE2QWQ2.
KOiK04468.
OMAiDDGFEKN.
OrthoDBiEOG091G05X6.
TreeFamiTF315210.

Enzyme and pathway databases

ReactomeiR-CFA-4086398. Ca2+ pathway.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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]
ProtoNetiSearch...

Entry informationi

Entry nameiNLK_CANLF
AccessioniPrimary (citable) accession number: E2QWQ2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 19, 2011
Last sequence update: November 30, 2010
Last modified: September 7, 2016
This is version 42 of the entry and version 1 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.