E2QWQ2 (NLK_CANFA) Reviewed, UniProtKB/Swiss-Prot
Last modified March 19, 2014. Version 25. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein kinase NLK
|Organism||Canis familiaris (Dog) (Canis lupus familiaris) [Reference proteome]|
|Taxonomic identifier||9615 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Carnivora › Caniformia › Canidae › Canis ›|
|Sequence length||527 AA.|
|Protein existence||Inferred from homology|
General annotation (Comments)
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.
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
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.
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.
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.
Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme By similarity.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 527||527||Serine/threonine-protein kinase NLK||PRO_0000413530|
|Domain||138 – 427||290||Protein kinase|
|Nucleotide binding||144 – 152||9||ATP By similarity|
|Region||1 – 304||304||Required for interaction with TAB2 By similarity|
|Region||1 – 125||125||Sufficient for interaction with DAPK3 By similarity|
|Region||124 – 416||293||Sufficient for interaction with DAPK3 By similarity|
|Region||428 – 527||100||Required for homodimerization and kinase activation and localization to the nucleus By similarity|
|Region||434 – 527||94||Required for interaction with TAB2 By similarity|
|Motif||298 – 300||3||TQE|
|Compositional bias||22 – 25||4||Poly-Ala|
|Compositional bias||27 – 34||8||Poly-His|
|Compositional bias||42 – 48||7||Poly-His|
|Compositional bias||71 – 83||13||Poly-Ala|
|Compositional bias||106 – 111||6||Poly-Ala|
|Compositional bias||115 – 119||5||Poly-Ala|
|Active site||264||1||Proton acceptor By similarity|
|Binding site||167||1||ATP By similarity|
Amino acid modifications
|Modified residue||298||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||522||1||Phosphoserine By similarity|
|||"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. Lander E.S.
Nature 438:803-819(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|AAEX02035279 Genomic DNA. No translation available.|
|RefSeq||XP_868108.2. XM_863015.3. |
3D structure databases
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSCAFT00000029610; ENSCAFP00000027521; ENSCAFG00000018650. |
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS01351. MAPK. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: E2QWQ2|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families