NLK_BOVIN
ID NLK_BOVIN Reviewed; 534 AA.
AC E1BMN8;
DT 19-OCT-2011, integrated into UniProtKB/Swiss-Prot.
DT 19-OCT-2011, sequence version 2.
DT 03-AUG-2022, entry version 53.
DE RecName: Full=Serine/threonine-protein kinase NLK;
DE EC=2.7.11.24;
DE AltName: Full=Nemo-like kinase;
GN Name=NLK;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford;
RX PubMed=19390049; DOI=10.1126/science.1169588;
RG The bovine genome sequencing and analysis consortium;
RT "The genome sequence of taurine cattle: a window to ruminant biology and
RT evolution.";
RL Science 324:522-528(2009).
CC -!- FUNCTION: Serine/threonine-protein kinase that regulates a number of
CC transcription factors with key roles in cell fate determination.
CC Positive effector of the non-canonical Wnt signaling pathway, acting
CC downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Activation of this pathway
CC causes binding to and phosphorylation of the histone methyltransferase
CC SETDB1. The NLK-SETDB1 complex subsequently interacts with PPARG,
CC leading to methylation of PPARG target promoters at histone H3K9 and
CC transcriptional silencing. The resulting loss of PPARG target gene
CC transcription inhibits adipogenesis and promotes osteoblastogenesis in
CC mesenchymal stem cells (MSCs). Negative regulator of the canonical
CC Wnt/beta-catenin signaling pathway. Binds to and phosphorylates
CC TCF7L2/TCF4 and LEF1, promoting the dissociation of the
CC TCF7L2/LEF1/beta-catenin complex from DNA, as well as the
CC ubiquitination and subsequent proteolysis of LEF1. Together these
CC effects inhibit the transcriptional activation of canonical Wnt/beta-
CC catenin target genes. Negative regulator of the Notch signaling
CC pathway. Binds to and phosphorylates NOTCH1, thereby preventing the
CC formation of a transcriptionally active ternary complex of NOTCH1,
CC RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of
CC transcription factors. Phosphorylation of MYB leads to its subsequent
CC proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their
CC interaction with the coactivator CREBBP. Other transcription factors
CC may also be inhibited by direct phosphorylation of CREBBP itself. Acts
CC downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in
CC turn required for activation of NLK by MAP3K7/TAK1. Upon IL1B stimulus,
CC cooperates with ATF5 to activate the transactivation activity of C/EBP
CC subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein
CC levels in a kinase-independent manner. {ECO:0000250|UniProtKB:O54949,
CC ECO:0000250|UniProtKB:Q9UBE8}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.24;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.24;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Activated by the non-canonical Wnt signaling
CC pathway, in which WNT5A leads to activation of MAP3K7/TAK1 and HIPK2,
CC which subsequently phosphorylates and activates this protein. Activated
CC by dimerization and subsequent intermolecular autophosphorylation on
CC Thr-305. Other cytokines such as IL6 may also activate this regulatory
CC circuit (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Homodimerization is required for intermolecular
CC autophosphorylation, kinase activation and nuclear localization (By
CC similarity). May interact with components of cullin-RING-based SCF
CC (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes (By
CC similarity). Interacts with LEF1, MEF2A, MYBL1 and MYBL2 (By
CC similarity). Interacts with the upstream activating kinases HIPK2 and
CC MAP3K7/TAK1. Interaction with MAP3K7/TAK1 seems to be indirect, and may
CC be mediated by other proteins such as STAT3, TAB1 and TAB2. Interacts
CC with and phosphorylates a number of transcription factors including
CC FOXO1, FOXO3, FOXO4, MYB, NOTCH1 and TCF7L2/TCF4. Interacts with
CC DAPK3/ZIPK, and this interaction may disrupt interaction with
CC transcription factors such as TCF7L2/TCF4. Forms a transcriptional
CC repressor complex with CHD7, PPARG and SETDB1. Interacts with
CC RNF138/NARF (By similarity). Interacts with ATF5; the interaction
CC stabilizes ATF5 at the protein level in a kinase-independent manner (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:O54949,
CC ECO:0000250|UniProtKB:Q9UBE8}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC Note=Predominantly nuclear. A smaller fraction is cytoplasmic (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: Contains a TQE activation loop motif in which
CC autophosphorylation of the threonine residue (Thr-305) is sufficient
CC for kinase activation. This mode of activation contrasts with that of
CC classical MAP kinases, which contain a TXY activation loop motif in
CC which phosphorylation of both the threonine and tyrosine residues is
CC required for kinase activation (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated on Thr-305. Intermolecular autophosphorylation on
CC Thr-305 activates the enzyme (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP kinase subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AAFC03038599; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAFC03038600; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAFC03038601; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAFC03117551; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAFC03125057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; E1BMN8; -.
DR SMR; E1BMN8; -.
DR STRING; 9913.ENSBTAP00000019742; -.
DR PaxDb; E1BMN8; -.
DR PRIDE; E1BMN8; -.
DR eggNOG; KOG0664; Eukaryota.
DR InParanoid; E1BMN8; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004707; F:MAP kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 3: Inferred from homology;
KW ATP-binding; Cytoplasm; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Wnt signaling pathway.
FT CHAIN 1..534
FT /note="Serine/threonine-protein kinase NLK"
FT /id="PRO_0000413529"
FT DOMAIN 145..434
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 8..311
FT /note="Required for interaction with TAB2"
FT /evidence="ECO:0000250"
FT REGION 8..132
FT /note="Sufficient for interaction with DAPK3"
FT /evidence="ECO:0000250"
FT REGION 29..79
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 97..147
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 131..423
FT /note="Sufficient for interaction with DAPK3"
FT /evidence="ECO:0000250"
FT REGION 435..534
FT /note="Required for homodimerization and kinase activation
FT and localization to the nucleus"
FT /evidence="ECO:0000250"
FT REGION 441..534
FT /note="Required for interaction with TAB2"
FT /evidence="ECO:0000250"
FT MOTIF 305..307
FT /note="TQE"
FT COMPBIAS 32..60
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 271
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 151..159
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 174
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 305
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9UBE8"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBE8"
SQ SEQUENCE 534 AA; 59339 MW; 02F602E8141D57BF CRC64;
MPNVFQNLVS CKRVFRELKM AAYNGGTSAA AAGHHHHHHH HLPHLPPPHL HHHHHPQHHL
HPGSAAAVHP VQQHTSSAAA AAAAAAAAAA MLNPGQQQPY FPSPAPGQAP GPAAAAPAQV
QAAAAATVKA HHHQHSHHPQ QQLDIEPDRP IGYGAFGVVW SVTDPRDGKR VALKKMPNVF
QNLVSCKRVF RELKMLCFFK HDNVLSALDI LQPPHIDYFE EIYVVTELMQ SDLHKIIVSP
QPLSSDHVKV FLYQILRGLK YLHSAGILHR DIKPGNLLVN SNCVLKICDF GLARVEELDE
SRHMTQEVVT QYYRAPEILM GSRHYSNAID IWSVGCIFAE LLGRRILFQA QSPIQQLDLI
TDLLGTPSLE AMRTACEGAK AHILRGPHKQ PSLPVLYTLS SQATHEAVHL LCRMLVFDPS
KRISAKDALA HPYLDEGRLR YHTCMCKCCF STSTGRVYTS DFEPVTNPKF DDTFEKNLSS
VRQVKEIIHQ FILEQQKGNR VPLCINPQSA AFKSFISSTV AQPSEMPPSP LVWE
