NLK_HUMAN
ID NLK_HUMAN Reviewed; 527 AA.
AC Q9UBE8; B2RCX1; Q2PNI9; Q6P2A3;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 03-NOV-2009, sequence version 2.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Serine/threonine-protein kinase NLK;
DE EC=2.7.11.24;
DE AltName: Full=Nemo-like kinase;
DE AltName: Full=Protein LAK1;
GN Name=NLK; Synonyms=LAK1 {ECO:0000312|EMBL:AAD56013.1};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000312|EMBL:AAF04857.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta {ECO:0000269|PubMed:10863097};
RX PubMed=10863097; DOI=10.1016/s0378-1119(00)00188-8;
RA Kehrer-Sawatzki H., Moschgath E., Maier C., Legius E., Elgar G., Krone W.;
RT "Characterization of the Fugu rubripes NLK and FN5 genes flanking the NF1
RT (Neurofibromatosis type 1) gene in the 5' direction and mapping of the
RT human counterparts.";
RL Gene 251:63-71(2000).
RN [2] {ECO:0000312|EMBL:AAD56013.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=T-cell;
RA Wang C., Lo H.;
RT "Cloning of human LAK1 cDNA.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Amygdala;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4] {ECO:0000312|EMBL:AAD56013.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=12482967; DOI=10.1128/mcb.23.1.131-139.2003;
RA Ishitani T., Kishida S., Hyodo-Miura J., Ueno N., Yasuda J., Waterman M.,
RA Shibuya H., Moon R.T., Ninomiya-Tsuji J., Matsumoto K.;
RT "The TAK1-NLK mitogen-activated protein kinase cascade functions in the
RT Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.";
RL Mol. Cell. Biol. 23:131-139(2003).
RN [7]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=15004007; DOI=10.1101/gad.1166904;
RA Ohkawara B., Shirakabe K., Hyodo-Miura J., Matsuo R., Ueno N.,
RA Matsumoto K., Shibuya H.;
RT "Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm
RT induction.";
RL Genes Dev. 18:381-386(2004).
RN [8] {ECO:0000305}
RP INTERACTION WITH MYB AND HIPK2.
RX PubMed=15082531; DOI=10.1101/gad.1170604;
RA Kanei-Ishii C., Ninomiya-Tsuji J., Tanikawa J., Nomura T., Ishitani T.,
RA Kishida S., Kokura K., Kurahashi T., Ichikawa-Iwata E., Kim Y.,
RA Matsumoto K., Ishii S.;
RT "Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via
RT TAK1, HIPK2, and NLK.";
RL Genes Dev. 18:816-829(2004).
RN [9]
RP FUNCTION.
RX PubMed=14960582; DOI=10.1074/jbc.m307801200;
RA Smit L., Baas A., Kuipers J., Korswagen H., van de Wetering M., Clevers H.;
RT "Wnt activates the Tak1/Nemo-like kinase pathway.";
RL J. Biol. Chem. 279:17232-17240(2004).
RN [10]
RP FUNCTION, AUTOPHOSPHORYLATION, INTERACTION WITH MAP3K7 AND STAT3, AND
RP SUBCELLULAR LOCATION.
RX PubMed=15764709; DOI=10.1073/pnas.0500679102;
RA Kojima H., Sasaki T., Ishitani T., Iemura S., Zhao H., Kaneko S.,
RA Kunimoto H., Natsume T., Matsumoto K., Nakajima K.;
RT "STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-
RT stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:4524-4529(2005).
RN [11]
RP INTERACTION WITH RNF138 AND TCF7L2.
RX PubMed=16714285; DOI=10.1074/jbc.m602089200;
RA Yamada M., Ohnishi J., Ohkawara B., Iemura S., Satoh K., Hyodo-Miura J.,
RA Kawachi K., Natsume T., Shibuya H.;
RT "NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates
RT the ubiquitylation and degradation of T cell factor/lymphoid enhancer
RT factor (TCF/LEF).";
RL J. Biol. Chem. 281:20749-20760(2006).
RN [12]
RP RETRACTED PAPER.
RX PubMed=17952062; DOI=10.1038/ncb1647;
RA Takada I., Mihara M., Suzawa M., Ohtake F., Kobayashi S., Igarashi M.,
RA Youn M.Y., Takeyama K., Nakamura T., Mezaki Y., Takezawa S., Yogiashi Y.,
RA Kitagawa H., Yamada G., Takada S., Minami Y., Shibuya H., Matsumoto K.,
RA Kato S.;
RT "A histone lysine methyltransferase activated by non-canonical Wnt
RT signalling suppresses PPAR-gamma transactivation.";
RL Nat. Cell Biol. 9:1273-1285(2007).
RN [13]
RP RETRACTION NOTICE OF PUBMED:17952062.
RX PubMed=25358353; DOI=10.1038/ncb3069;
RA Takada I., Mihara M., Suzawa M., Ohtake F., Kobayashi S., Igarashi M.,
RA Youn M.Y., Takeyama K., Nakamura T., Mezaki Y., Takezawa S., Yogiashi Y.,
RA Kitagawa H., Yamada G., Takada S., Minami Y., Shibuya H., Matsumoto K.,
RA Kato S.;
RL Nat. Cell Biol. 16:1126-1126(2014).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-298 AND SER-522, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-298, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP FUNCTION, INTERACTION WITH FOXO1, AND MUTAGENESIS OF LYS-167.
RX PubMed=20061393; DOI=10.1074/jbc.m110.101824;
RA Kim S., Kim Y., Lee J., Chung J.;
RT "Regulation of FOXO1 by TAK1-Nemo-like kinase pathway.";
RL J. Biol. Chem. 285:8122-8129(2010).
RN [17]
RP FUNCTION, AND INTERACTION WITH NOTCH1.
RX PubMed=20118921; DOI=10.1038/ncb2028;
RA Ishitani T., Hirao T., Suzuki M., Isoda M., Ishitani S., Harigaya K.,
RA Kitagawa M., Matsumoto K., Itoh M.;
RT "Nemo-like kinase suppresses Notch signalling by interfering with formation
RT of the Notch active transcriptional complex.";
RL Nat. Cell Biol. 12:278-285(2010).
RN [18]
RP FUNCTION, AND INTERACTION WITH FOXO1; FOXO3 AND FOXO4.
RX PubMed=20874444; DOI=10.1089/ars.2010.3243;
RA Szypowska A.A., de Ruiter H., Meijer L.A.T., Smits L.M.M.,
RA Burgering B.M.T.;
RT "Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-
RT like kinase.";
RL Antioxid. Redox Signal. 14:563-578(2011).
RN [19]
RP FUNCTION, AND INTERACTION WITH DAPK3 AND TCF7L2.
RX PubMed=21454679; DOI=10.1074/jbc.m110.189829;
RA Togi S., Ikeda O., Kamitani S., Nakasuji M., Sekine Y., Muromoto R.,
RA Nanbo A., Oritani K., Kawai T., Akira S., Matsuda T.;
RT "Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-
RT catenin signaling through interaction with Nemo-like kinase and T-cell
RT factor 4 (NLK/TCF4).";
RL J. Biol. Chem. 286:19170-19177(2011).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-298, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP FUNCTION, AND INTERACTION WITH ATF5.
RX PubMed=25512613; DOI=10.1128/mcb.01228-14;
RA Zhang Z.Y., Li S.Z., Zhang H.H., Wu Q.R., Gong J., Liang T., Gao L.,
RA Xing N.N., Liu W.B., Du R.L., Zhang X.D.;
RT "Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the
RT interleukin-1beta-stimulated C/EBP signaling pathway.";
RL Mol. Cell. Biol. 35:778-788(2015).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] THR-343.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
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 (PubMed:25512613).
CC {ECO:0000250|UniProtKB:O54949, ECO:0000269|PubMed:12482967,
CC ECO:0000269|PubMed:14960582, ECO:0000269|PubMed:15004007,
CC ECO:0000269|PubMed:15764709, ECO:0000269|PubMed:20061393,
CC ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20874444,
CC ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:25512613}.
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 dimerization and subsequent
CC intermolecular autophosphorylation on Thr-298 (By similarity).
CC Activated by the non-canonical Wnt signaling pathway, in which WNT5A
CC treatment leads to activation of MAP3K7/TAK1 and HIPK2, which
CC subsequently phosphorylates and activates this protein. Other cytokines
CC such as IL6 may also activate this regulatory circuit. {ECO:0000250,
CC ECO:0000269|PubMed:12482967, ECO:0000269|PubMed:15004007}.
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. Interacts with RNF138/NARF.
CC Interacts with ATF5; the interaction stabilizes ATF5 at the protein
CC level in a kinase-independent manner (PubMed:25512613). {ECO:0000250,
CC ECO:0000269|PubMed:15082531, ECO:0000269|PubMed:15764709,
CC ECO:0000269|PubMed:16714285, ECO:0000269|PubMed:20061393,
CC ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20874444,
CC ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:25512613}.
CC -!- INTERACTION:
CC Q9UBE8; P54253: ATXN1; NbExp=4; IntAct=EBI-366978, EBI-930964;
CC Q9UBE8; O43293: DAPK3; NbExp=3; IntAct=EBI-366978, EBI-77293;
CC Q9UBE8; P28799: GRN; NbExp=7; IntAct=EBI-366978, EBI-747754;
CC Q9UBE8; P42858: HTT; NbExp=3; IntAct=EBI-366978, EBI-466029;
CC Q9UBE8; Q9BYR5: KRTAP4-2; NbExp=3; IntAct=EBI-366978, EBI-10172511;
CC Q9UBE8; Q6L8G9: KRTAP5-6; NbExp=3; IntAct=EBI-366978, EBI-10250562;
CC Q9UBE8; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-366978, EBI-3958099;
CC Q9UBE8; Q9UHB4: NDOR1; NbExp=3; IntAct=EBI-366978, EBI-10249760;
CC Q9UBE8; Q2TAL8: QRICH1; NbExp=3; IntAct=EBI-366978, EBI-2798044;
CC Q9UBE8; Q96PM5: RCHY1; NbExp=5; IntAct=EBI-366978, EBI-947779;
CC Q9UBE8; Q13485: SMAD4; NbExp=6; IntAct=EBI-366978, EBI-347263;
CC Q9UBE8; Q14186: TFDP1; NbExp=2; IntAct=EBI-366978, EBI-749713;
CC Q9UBE8; Q9H4I2: ZHX3; NbExp=4; IntAct=EBI-366978, EBI-948582;
CC Q9UBE8; Q9H4I2-2: ZHX3; NbExp=3; IntAct=EBI-366978, EBI-10693326;
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.
CC -!- PTM: Phosphorylated on Thr-298. Intermolecular autophosphorylation on
CC Thr-298 activates the enzyme.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP kinase subfamily. {ECO:0000305}.
CC -!- CAUTION: Was reported to form a transcriptional repressor complex with
CC CHD7 and SETDB1 involved in PPARG repression (PubMed:17952062).
CC However, this work was later retracted (PubMed:25358353).
CC {ECO:0000269|PubMed:17952062, ECO:0000269|PubMed:25358353}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD56013.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAF04857.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=ABC40748.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAG37718.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF197898; AAF04857.1; ALT_INIT; mRNA.
DR EMBL; AF180819; AAD56013.1; ALT_INIT; mRNA.
DR EMBL; AK315315; BAG37718.1; ALT_INIT; mRNA.
DR EMBL; DQ316259; ABC40748.1; ALT_INIT; Genomic_DNA.
DR EMBL; BC064663; AAH64663.2; -; mRNA.
DR CCDS; CCDS11224.2; -.
DR RefSeq; NP_057315.3; NM_016231.4.
DR AlphaFoldDB; Q9UBE8; -.
DR SMR; Q9UBE8; -.
DR BioGRID; 119685; 64.
DR CORUM; Q9UBE8; -.
DR IntAct; Q9UBE8; 41.
DR MINT; Q9UBE8; -.
DR STRING; 9606.ENSP00000384625; -.
DR BindingDB; Q9UBE8; -.
DR ChEMBL; CHEMBL5364; -.
DR DrugCentral; Q9UBE8; -.
DR GuidetoPHARMACOLOGY; 2125; -.
DR iPTMnet; Q9UBE8; -.
DR PhosphoSitePlus; Q9UBE8; -.
DR BioMuta; NLK; -.
DR DMDM; 262527551; -.
DR EPD; Q9UBE8; -.
DR jPOST; Q9UBE8; -.
DR MassIVE; Q9UBE8; -.
DR PaxDb; Q9UBE8; -.
DR PeptideAtlas; Q9UBE8; -.
DR PRIDE; Q9UBE8; -.
DR ProteomicsDB; 83953; -.
DR Antibodypedia; 13947; 389 antibodies from 37 providers.
DR DNASU; 51701; -.
DR Ensembl; ENST00000407008.8; ENSP00000384625.3; ENSG00000087095.13.
DR GeneID; 51701; -.
DR KEGG; hsa:51701; -.
DR MANE-Select; ENST00000407008.8; ENSP00000384625.3; NM_016231.5; NP_057315.3.
DR UCSC; uc010crj.4; human.
DR CTD; 51701; -.
DR DisGeNET; 51701; -.
DR GeneCards; NLK; -.
DR HGNC; HGNC:29858; NLK.
DR HPA; ENSG00000087095; Tissue enhanced (retina).
DR MIM; 609476; gene.
DR neXtProt; NX_Q9UBE8; -.
DR OpenTargets; ENSG00000087095; -.
DR PharmGKB; PA134914500; -.
DR VEuPathDB; HostDB:ENSG00000087095; -.
DR eggNOG; KOG0664; Eukaryota.
DR GeneTree; ENSGT00940000158363; -.
DR InParanoid; Q9UBE8; -.
DR OMA; HSCMCRC; -.
DR OrthoDB; 741207at2759; -.
DR PhylomeDB; Q9UBE8; -.
DR TreeFam; TF315210; -.
DR PathwayCommons; Q9UBE8; -.
DR Reactome; R-HSA-4086398; Ca2+ pathway.
DR SignaLink; Q9UBE8; -.
DR SIGNOR; Q9UBE8; -.
DR BioGRID-ORCS; 51701; 17 hits in 1114 CRISPR screens.
DR ChiTaRS; NLK; human.
DR GeneWiki; NLK; -.
DR GenomeRNAi; 51701; -.
DR Pharos; Q9UBE8; Tchem.
DR PRO; PR:Q9UBE8; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9UBE8; protein.
DR Bgee; ENSG00000087095; Expressed in middle temporal gyrus and 187 other tissues.
DR ExpressionAtlas; Q9UBE8; baseline and differential.
DR Genevisible; Q9UBE8; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0004707; F:MAP kinase activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
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; ISS:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042501; P:serine phosphorylation of STAT protein; ISS:UniProtKB.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007223; P:Wnt signaling pathway, calcium modulating pathway; TAS:Reactome.
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 1: Evidence at protein level;
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_0000186336"
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:0000269|PubMed:21454679"
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:0000269|PubMed:21454679"
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:0000305"
FT MOD_RES 298
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 522
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT VARIANT 177
FT /note="V -> A (in dbSNP:rs11871287)"
FT /id="VAR_019549"
FT VARIANT 343
FT /note="A -> T (in a glioblastoma multiforme sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042273"
FT MUTAGEN 167
FT /note="K->N: Abrogates kinase activity."
FT /evidence="ECO:0000269|PubMed:20061393"
FT CONFLICT 25
FT /note="A -> T (in Ref. 5; AAH64663)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 527 AA; 58283 MW; CE6AEBA7D8133989 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 YTSDFEPVTN PKFDDTFEKN LSSVRQVKEI
IHQFILEQQK GNRVPLCINP QSAAFKSFIS STVAQPSEMP PSPLVWE
