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NLK_RAT
ID   NLK_RAT                 Reviewed;         527 AA.
AC   D3ZSZ3;
DT   19-OCT-2011, integrated into UniProtKB/Swiss-Prot.
DT   20-APR-2010, sequence version 1.
DT   03-AUG-2022, entry version 80.
DE   RecName: Full=Serine/threonine-protein kinase NLK;
DE            EC=2.7.11.24;
DE   AltName: Full=Nemo-like kinase;
GN   Name=Nlk;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Brown Norway;
RX   PubMed=15057822; DOI=10.1038/nature02426;
RA   Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA   Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA   Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA   Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA   Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA   Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA   Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA   Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA   Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA   Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA   Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA   Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA   Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA   Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA   Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA   Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA   Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA   Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA   Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA   Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA   Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA   Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA   Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA   Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA   Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA   Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA   Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA   Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA   Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA   Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA   Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA   Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA   Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA   Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA   Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA   Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA   Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA   Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA   Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA   Mockrin S., Collins F.S.;
RT   "Genome sequence of the Brown Norway rat yields insights into mammalian
RT   evolution.";
RL   Nature 428:493-521(2004).
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-298. 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|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-298) 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-298. Intermolecular autophosphorylation on
CC       Thr-298 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}.
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DR   EMBL; AABR03073152; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   RefSeq; NP_001178853.1; NM_001191924.1.
DR   AlphaFoldDB; D3ZSZ3; -.
DR   SMR; D3ZSZ3; -.
DR   STRING; 10116.ENSRNOP00000011726; -.
DR   iPTMnet; D3ZSZ3; -.
DR   PhosphoSitePlus; D3ZSZ3; -.
DR   jPOST; D3ZSZ3; -.
DR   PaxDb; D3ZSZ3; -.
DR   PeptideAtlas; D3ZSZ3; -.
DR   PRIDE; D3ZSZ3; -.
DR   Ensembl; ENSRNOT00000011726; ENSRNOP00000011726; ENSRNOG00000008704.
DR   GeneID; 497961; -.
DR   KEGG; rno:497961; -.
DR   CTD; 51701; -.
DR   RGD; 1561602; Nlk.
DR   eggNOG; KOG0664; Eukaryota.
DR   GeneTree; ENSGT00940000158363; -.
DR   HOGENOM; CLU_000288_133_2_1; -.
DR   InParanoid; D3ZSZ3; -.
DR   OMA; HSCMCRC; -.
DR   OrthoDB; 741207at2759; -.
DR   PhylomeDB; D3ZSZ3; -.
DR   TreeFam; TF315210; -.
DR   Reactome; R-RNO-4086398; Ca2+ pathway.
DR   PRO; PR:D3ZSZ3; -.
DR   Proteomes; UP000002494; Chromosome 10.
DR   Bgee; ENSRNOG00000008704; Expressed in frontal cortex and 19 other tissues.
DR   Genevisible; D3ZSZ3; RN.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; ISO:RGD.
DR   GO; GO:0005524; F:ATP binding; ISO:RGD.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:RGD.
DR   GO; GO:0000287; F:magnesium ion binding; ISO:RGD.
DR   GO; GO:0004707; F:MAP kinase activity; ISO:RGD.
DR   GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:RGD.
DR   GO; GO:0042169; F:SH2 domain binding; ISO:RGD.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR   GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
DR   GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISO:RGD.
DR   GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:RGD.
DR   GO; GO:0046777; P:protein autophosphorylation; ISO:RGD.
DR   GO; GO:0006468; P:protein phosphorylation; ISO:RGD.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
DR   GO; GO:0042501; P:serine phosphorylation of STAT protein; ISO:RGD.
DR   GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISO:RGD.
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..527
FT                   /note="Serine/threonine-protein kinase NLK"
FT                   /id="PRO_0000413531"
FT   DOMAIN          138..427
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..304
FT                   /note="Required for interaction with TAB2"
FT                   /evidence="ECO:0000250"
FT   REGION          1..125
FT                   /note="Sufficient for interaction with DAPK3"
FT                   /evidence="ECO:0000250"
FT   REGION          22..72
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          90..139
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          124..416
FT                   /note="Sufficient for interaction with DAPK3"
FT                   /evidence="ECO:0000250"
FT   REGION          428..527
FT                   /note="Required for homodimerization and kinase activation
FT                   and localization to the nucleus"
FT                   /evidence="ECO:0000250"
FT   REGION          434..527
FT                   /note="Required for interaction with TAB2"
FT                   /evidence="ECO:0000250"
FT   MOTIF           298..300
FT                   /note="TQE"
FT   COMPBIAS        25..53
FT                   /note="Basic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        264
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         144..152
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         167
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         298
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UBE8"
FT   MOD_RES         522
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UBE8"
SQ   SEQUENCE   527 AA;  58313 MW;  CE6D5DCCB9133989 CRC64;
     MSLCGTRANA KMMAAYNGGT SAAAAGHHHH HHHHLPHLPP PHLHHHHHPQ HHLHPGSAAA
     VHPVQQHTSS AAAAAAAAAA AAAMLNPGQQ QPYFPSPAPG QAPGPAAAAP AQVQAAAAAT
     VKAHHHQHSH HPQQQLDIEP DRPIGYGAFG VVWSVTDPRD GKRVALKKMP NVFQNLVSCK
     RVFRELKMLC FFKHDNVLSA LDILQPPHID YFEEIYVVTE LMQSDLHKII VSPQPLSSDH
     VKVFLYQILR GLKYLHSAGI LHRDIKPGNL LVNSNCVLKI CDFGLARVEE LDESRHMTQE
     VVTQYYRAPE ILMGSRHYSN AIDIWSVGCI FAELLGRRIL FQAQSPIQQL DLITDLLGTP
     SLEAMRTACE GAKAHILRGP HKQPSLPVLY TLSSQATHEA VHLLCRMLVF DPSKRISAKD
     ALAHPYLDEG RLRYHTCMCK CCFSTSTGRV YTSDFEPVTN PKFDDTFEKN LSSVRQVKEI
     IHQFILEQQK GNRVPLCINP QSAAFKSFIS STVAQPSEMP PSPLVWE
 
 
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