NLK_CANLF
ID NLK_CANLF Reviewed; 527 AA.
AC E2QWQ2;
DT 19-OCT-2011, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 1.
DT 03-AUG-2022, entry version 70.
DE RecName: Full=Serine/threonine-protein kinase NLK;
DE EC=2.7.11.24;
DE AltName: Full=Nemo-like kinase;
GN Name=NLK;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Boxer;
RX PubMed=16341006; DOI=10.1038/nature04338;
RA Lindblad-Toh K., Wade C.M., Mikkelsen T.S., Karlsson E.K., Jaffe D.B.,
RA Kamal M., Clamp M., Chang J.L., Kulbokas E.J. III, Zody M.C., Mauceli E.,
RA Xie X., Breen M., Wayne R.K., Ostrander E.A., Ponting C.P., Galibert F.,
RA Smith D.R., deJong P.J., Kirkness E.F., Alvarez P., Biagi T., Brockman W.,
RA Butler J., Chin C.-W., Cook A., Cuff J., Daly M.J., DeCaprio D., Gnerre S.,
RA Grabherr M., Kellis M., Kleber M., Bardeleben C., Goodstadt L., Heger A.,
RA Hitte C., Kim L., Koepfli K.-P., Parker H.G., Pollinger J.P.,
RA Searle S.M.J., Sutter N.B., Thomas R., Webber C., Baldwin J., Abebe A.,
RA Abouelleil A., Aftuck L., Ait-Zahra M., Aldredge T., Allen N., An P.,
RA Anderson S., Antoine C., Arachchi H., Aslam A., Ayotte L., Bachantsang P.,
RA Barry A., Bayul T., Benamara M., Berlin A., Bessette D., Blitshteyn B.,
RA Bloom T., Blye J., Boguslavskiy L., Bonnet C., Boukhgalter B., Brown A.,
RA Cahill P., Calixte N., Camarata J., Cheshatsang Y., Chu J., Citroen M.,
RA Collymore A., Cooke P., Dawoe T., Daza R., Decktor K., DeGray S.,
RA Dhargay N., Dooley K., Dooley K., Dorje P., Dorjee K., Dorris L.,
RA Duffey N., Dupes A., Egbiremolen O., Elong R., Falk J., Farina A., Faro S.,
RA Ferguson D., Ferreira P., Fisher S., FitzGerald M., Foley K., Foley C.,
RA Franke A., Friedrich D., Gage D., Garber M., Gearin G., Giannoukos G.,
RA Goode T., Goyette A., Graham J., Grandbois E., Gyaltsen K., Hafez N.,
RA Hagopian D., Hagos B., Hall J., Healy C., Hegarty R., Honan T., Horn A.,
RA Houde N., Hughes L., Hunnicutt L., Husby M., Jester B., Jones C., Kamat A.,
RA Kanga B., Kells C., Khazanovich D., Kieu A.C., Kisner P., Kumar M.,
RA Lance K., Landers T., Lara M., Lee W., Leger J.-P., Lennon N., Leuper L.,
RA LeVine S., Liu J., Liu X., Lokyitsang Y., Lokyitsang T., Lui A.,
RA Macdonald J., Major J., Marabella R., Maru K., Matthews C., McDonough S.,
RA Mehta T., Meldrim J., Melnikov A., Meneus L., Mihalev A., Mihova T.,
RA Miller K., Mittelman R., Mlenga V., Mulrain L., Munson G., Navidi A.,
RA Naylor J., Nguyen T., Nguyen N., Nguyen C., Nguyen T., Nicol R., Norbu N.,
RA Norbu C., Novod N., Nyima T., Olandt P., O'Neill B., O'Neill K., Osman S.,
RA Oyono L., Patti C., Perrin D., Phunkhang P., Pierre F., Priest M.,
RA Rachupka A., Raghuraman S., Rameau R., Ray V., Raymond C., Rege F.,
RA Rise C., Rogers J., Rogov P., Sahalie J., Settipalli S., Sharpe T.,
RA Shea T., Sheehan M., Sherpa N., Shi J., Shih D., Sloan J., Smith C.,
RA Sparrow T., Stalker J., Stange-Thomann N., Stavropoulos S., Stone C.,
RA Stone S., Sykes S., Tchuinga P., Tenzing P., Tesfaye S., Thoulutsang D.,
RA Thoulutsang Y., Topham K., Topping I., Tsamla T., Vassiliev H.,
RA Venkataraman V., Vo A., Wangchuk T., Wangdi T., Weiand M., Wilkinson J.,
RA Wilson A., Yadav S., Yang S., Yang X., Young G., Yu Q., Zainoun J.,
RA Zembek L., Zimmer A., Lander E.S.;
RT "Genome sequence, comparative analysis and haplotype structure of the
RT domestic dog.";
RL Nature 438:803-819(2005).
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; AAEX02035279; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_868108.2; XM_863015.4.
DR AlphaFoldDB; E2QWQ2; -.
DR SMR; E2QWQ2; -.
DR STRING; 9612.ENSCAFP00000027521; -.
DR PaxDb; E2QWQ2; -.
DR PRIDE; E2QWQ2; -.
DR Ensembl; ENSCAFT00000075065; ENSCAFP00000053136; ENSCAFG00000018650.
DR Ensembl; ENSCAFT00030026163; ENSCAFP00030022847; ENSCAFG00030014127.
DR Ensembl; ENSCAFT00040036745; ENSCAFP00040032009; ENSCAFG00040019853.
DR Ensembl; ENSCAFT00845027063; ENSCAFP00845021296; ENSCAFG00845015154.
DR GeneID; 491160; -.
DR KEGG; cfa:491160; -.
DR CTD; 51701; -.
DR VEuPathDB; HostDB:ENSCAFG00845015154; -.
DR VGNC; VGNC:43841; NLK.
DR eggNOG; KOG0664; Eukaryota.
DR GeneTree; ENSGT00940000158363; -.
DR HOGENOM; CLU_000288_133_2_1; -.
DR InParanoid; E2QWQ2; -.
DR OMA; HSCMCRC; -.
DR OrthoDB; 741207at2759; -.
DR TreeFam; TF315210; -.
DR Reactome; R-CFA-4086398; Ca2+ pathway.
DR Proteomes; UP000002254; Chromosome 9.
DR Bgee; ENSCAFG00000018650; Expressed in occipital cortex and 46 other tissues.
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:0140297; F:DNA-binding transcription factor binding; IEA:Ensembl.
DR GO; GO:0000287; F:magnesium ion binding; IEA:Ensembl.
DR GO; GO:0004707; F:MAP kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0042169; F:SH2 domain binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:Ensembl.
DR GO; GO:0042501; P:serine phosphorylation of STAT protein; IEA:Ensembl.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
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_0000413530"
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..140
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; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9UBE8"
FT MOD_RES 522
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBE8"
SQ SEQUENCE 527 AA; 58297 MW; D6D148A7D801BB19 CRC64;
MSLCGARANA 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 YTSDFEPITN PKFDDTFEKN LSSVRQVKEI
IHQFILEQQK GNRVPLCINP QSAAFKSFIS STVAQPSEMP PSPLVWE
