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   27-MAR-2024, entry version 59.
DE   RecName: Full=Serine/threonine-protein kinase NLK;
DE            EC=2.7.11.24 {ECO:0000250|UniProtKB:O54949};
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. Negative regulator of the
CC       canonical Wnt/beta-catenin signaling pathway. Binds to and
CC       phosphorylates 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. Acts as an inhibitor of the
CC       mTORC1 complex in response to osmotic stress by mediating
CC       phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1
CC       complex to lysosomes. {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         Evidence={ECO:0000250|UniProtKB:O54949};
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; Evidence={ECO:0000250|UniProtKB:O54949};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:O54949};
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|UniProtKB:O54949}.
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|UniProtKB:O54949,
CC       ECO:0000250|UniProtKB:Q9UBE8}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:O54949}. Cytoplasm
CC       {ECO:0000250|UniProtKB:O54949}. Note=Predominantly nuclear. A smaller
CC       fraction is cytoplasmic. {ECO:0000250|UniProtKB:O54949}.
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. {ECO:0000250|UniProtKB:O54949}.
CC   -!- PTM: Phosphorylated on Thr-305. Intermolecular autophosphorylation on
CC       Thr-305 activates the enzyme. {ECO:0000250|UniProtKB:O54949}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. MAP kinase subfamily. {ECO:0000305}.
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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; 9913-ENSBTAP00000019742; -.
DR   eggNOG; KOG0664; Eukaryota.
DR   InParanoid; E1BMN8; -.
DR   Proteomes; UP000009136; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004707; F:MAP kinase activity; IBA:GO_Central.
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:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:1904262; P:negative regulation of TORC1 signaling; ISS:UniProtKB.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd07853; STKc_NLK; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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   PANTHER; PTHR24055; MITOGEN-ACTIVATED PROTEIN KINASE; 1.
DR   PANTHER; PTHR24055:SF593; SIMILAR TO NEMO-LIKE KINASE; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 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|UniProtKB:O54949"
FT   REGION          8..132
FT                   /note="Sufficient for interaction with DAPK3"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UBE8"
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|UniProtKB:Q9UBE8"
FT   REGION          435..534
FT                   /note="Required for homodimerization and kinase activation
FT                   and localization to the nucleus"
FT                   /evidence="ECO:0000250|UniProtKB:O54949"
FT   REGION          441..534
FT                   /note="Required for interaction with TAB2"
FT                   /evidence="ECO:0000250|UniProtKB:O54949"
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
//