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Protein

Serine/threonine-protein kinase NLK

Gene

NLK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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 (PubMed:25512613).By similarity10 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Activity regulationi

Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298 (By similarity). Activated by the non-canonical Wnt signaling pathway, in which WNT5A treatment leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Other cytokines such as IL6 may also activate this regulatory circuit.By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei167ATPCurated1
Active sitei264Proton acceptorPROSITE-ProRule annotation1

Regions

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

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processTranscription, Transcription regulation, Wnt signaling pathway
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-4086398 Ca2+ pathway
SignaLinkiQ9UBE8
SIGNORiQ9UBE8

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase NLK (EC:2.7.11.24)
Alternative name(s):
Nemo-like kinase
Protein LAK1
Gene namesi
Name:NLK
Synonyms:LAK1Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000087095.12
HGNCiHGNC:29858 NLK
MIMi609476 gene
neXtProtiNX_Q9UBE8

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi167K → N: Abrogates kinase activity. 2 Publications1

Organism-specific databases

DisGeNETi51701
OpenTargetsiENSG00000087095
PharmGKBiPA134914500

Chemistry databases

ChEMBLiCHEMBL5364
GuidetoPHARMACOLOGYi2125

Polymorphism and mutation databases

BioMutaiNLK
DMDMi262527551

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001863361 – 527Serine/threonine-protein kinase NLKAdd BLAST527

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei298Phosphothreonine; by autocatalysisCombined sources1
Modified residuei522PhosphoserineCombined sources1

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9UBE8
PaxDbiQ9UBE8
PeptideAtlasiQ9UBE8
PRIDEiQ9UBE8
ProteomicsDBi83953

PTM databases

iPTMnetiQ9UBE8
PhosphoSitePlusiQ9UBE8

Expressioni

Gene expression databases

BgeeiENSG00000087095 Expressed in 207 organ(s), highest expression level in middle temporal gyrus
CleanExiHS_NLK
ExpressionAtlasiQ9UBE8 baseline and differential
GenevisibleiQ9UBE8 HS

Organism-specific databases

HPAiHPA018192
HPA056511

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. Interacts with ATF5; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner (PubMed:25512613).By similarity9 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi119685, 59 interactors
CORUMiQ9UBE8
IntActiQ9UBE8, 41 interactors
MINTiQ9UBE8
STRINGi9606.ENSP00000384625

Chemistry databases

BindingDBiQ9UBE8

Structurei

3D structure databases

ProteinModelPortaliQ9UBE8
SMRiQ9UBE8
ModBaseiSearch...
MobiDBiSearch...

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 DAPK31 PublicationAdd BLAST125
Regioni124 – 416Sufficient for interaction with DAPK31 PublicationAdd 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.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0664 Eukaryota
ENOG410XRAQ LUCA
GeneTreeiENSGT00910000144035
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiQ9UBE8
KOiK04468
OMAiMSSGAMD
OrthoDBiEOG091G05X6
PhylomeDBiQ9UBE8
TreeFamiTF315210

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR003527 MAP_kinase_CS
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS01351 MAPK, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

Q9UBE8-1 [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
YTSDFEPVTN PKFDDTFEKN LSSVRQVKEI IHQFILEQQK GNRVPLCINP
510 520
QSAAFKSFIS STVAQPSEMP PSPLVWE
Length:527
Mass (Da):58,283
Last modified:November 3, 2009 - v2
Checksum:iCE6AEBA7D8133989
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0YD75H0YD75_HUMAN
Mitogen-activated protein kinase
NLK
475Annotation score:
J3QSE9J3QSE9_HUMAN
Serine/threonine-protein kinase NLK
NLK
181Annotation score:

Sequence cautioni

The sequence AAD56013 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence AAF04857 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence ABC40748 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAG37718 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti25A → T in AAH64663 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_019549177V → A. Corresponds to variant dbSNP:rs11871287Ensembl.1
Natural variantiVAR_042273343A → T in a glioblastoma multiforme sample; somatic mutation. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF197898 mRNA Translation: AAF04857.1 Different initiation.
AF180819 mRNA Translation: AAD56013.1 Different initiation.
AK315315 mRNA Translation: BAG37718.1 Different initiation.
DQ316259 Genomic DNA Translation: ABC40748.1 Different initiation.
BC064663 mRNA Translation: AAH64663.2
CCDSiCCDS11224.2
RefSeqiNP_057315.3, NM_016231.4
UniGeneiHs.208759

Genome annotation databases

EnsembliENST00000407008; ENSP00000384625; ENSG00000087095
GeneIDi51701
KEGGihsa:51701
UCSCiuc010crj.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF197898 mRNA Translation: AAF04857.1 Different initiation.
AF180819 mRNA Translation: AAD56013.1 Different initiation.
AK315315 mRNA Translation: BAG37718.1 Different initiation.
DQ316259 Genomic DNA Translation: ABC40748.1 Different initiation.
BC064663 mRNA Translation: AAH64663.2
CCDSiCCDS11224.2
RefSeqiNP_057315.3, NM_016231.4
UniGeneiHs.208759

3D structure databases

ProteinModelPortaliQ9UBE8
SMRiQ9UBE8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119685, 59 interactors
CORUMiQ9UBE8
IntActiQ9UBE8, 41 interactors
MINTiQ9UBE8
STRINGi9606.ENSP00000384625

Chemistry databases

BindingDBiQ9UBE8
ChEMBLiCHEMBL5364
GuidetoPHARMACOLOGYi2125

PTM databases

iPTMnetiQ9UBE8
PhosphoSitePlusiQ9UBE8

Polymorphism and mutation databases

BioMutaiNLK
DMDMi262527551

Proteomic databases

EPDiQ9UBE8
PaxDbiQ9UBE8
PeptideAtlasiQ9UBE8
PRIDEiQ9UBE8
ProteomicsDBi83953

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000407008; ENSP00000384625; ENSG00000087095
GeneIDi51701
KEGGihsa:51701
UCSCiuc010crj.4 human

Organism-specific databases

CTDi51701
DisGeNETi51701
EuPathDBiHostDB:ENSG00000087095.12
GeneCardsiNLK
HGNCiHGNC:29858 NLK
HPAiHPA018192
HPA056511
MIMi609476 gene
neXtProtiNX_Q9UBE8
OpenTargetsiENSG00000087095
PharmGKBiPA134914500
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0664 Eukaryota
ENOG410XRAQ LUCA
GeneTreeiENSGT00910000144035
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiQ9UBE8
KOiK04468
OMAiMSSGAMD
OrthoDBiEOG091G05X6
PhylomeDBiQ9UBE8
TreeFamiTF315210

Enzyme and pathway databases

ReactomeiR-HSA-4086398 Ca2+ pathway
SignaLinkiQ9UBE8
SIGNORiQ9UBE8

Miscellaneous databases

ChiTaRSiNLK human
GeneWikiiNLK
GenomeRNAii51701
PROiPR:Q9UBE8
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000087095 Expressed in 207 organ(s), highest expression level in middle temporal gyrus
CleanExiHS_NLK
ExpressionAtlasiQ9UBE8 baseline and differential
GenevisibleiQ9UBE8 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR003527 MAP_kinase_CS
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS01351 MAPK, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNLK_HUMAN
AccessioniPrimary (citable) accession number: Q9UBE8
Secondary accession number(s): B2RCX1, Q2PNI9, Q6P2A3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: November 3, 2009
Last modified: November 7, 2018
This is version 173 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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Main funding by: National Institutes of Health

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