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 27-MAR-2024, entry version 202. DE RecName: Full=Serine/threonine-protein kinase NLK; DE EC=2.7.11.24 {ECO:0000269|PubMed:26588989}; 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 FUNCTION, AND 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 CATALYTIC ACTIVITY. RX PubMed=26588989; DOI=10.1101/gad.265116.115; RA Yuan H.X., Wang Z., Yu F.X., Li F., Russell R.C., Jewell J.L., Guan K.L.; RT "NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition."; RL Genes Dev. 29:2362-2376(2015). RN [22] 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 [23] 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 (PubMed:14960582, PubMed:12482967, PubMed:15004007, PubMed:15764709, CC PubMed:20061393, PubMed:20874444, PubMed:21454679). Positive effector CC of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, CC MAP3K7/TAK1 and HIPK2 (PubMed:15004007, PubMed:15764709). Negative CC regulator of the canonical Wnt/beta-catenin signaling pathway CC (PubMed:12482967). Binds to and phosphorylates TCF7L2/TCF4 and LEF1, CC promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from CC DNA, as well as the ubiquitination and subsequent proteolysis of LEF1 CC (PubMed:21454679). Together these effects inhibit the transcriptional CC activation of canonical Wnt/beta-catenin target genes (PubMed:12482967, CC PubMed:21454679). Negative regulator of the Notch signaling pathway CC (PubMed:20118921). Binds to and phosphorylates NOTCH1, thereby CC preventing the formation of a transcriptionally active ternary complex CC of NOTCH1, RBPJ/RBPSUH and MAML1 (PubMed:20118921). Negative regulator CC of the MYB family of transcription factors (PubMed:15082531). CC Phosphorylation of MYB leads to its subsequent proteolysis while CC phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the CC coactivator CREBBP (PubMed:15082531). Other transcription factors may CC also be inhibited by direct phosphorylation of CREBBP itself CC (PubMed:15082531). Acts downstream of IL6 and MAP3K7/TAK1 to CC phosphorylate STAT3, which is in turn required for activation of NLK by CC MAP3K7/TAK1 (PubMed:15004007, PubMed:15764709). Upon IL1B stimulus, CC cooperates with ATF5 to activate the transactivation activity of C/EBP CC subfamily members (PubMed:25512613). Phosphorylates ATF5 but also CC stabilizes ATF5 protein levels in a kinase-independent manner CC (PubMed:25512613). Acts as an inhibitor of the mTORC1 complex in CC response to osmotic stress by mediating phosphorylation of RPTOR, CC thereby preventing recruitment of the mTORC1 complex to lysosomes CC (PubMed:26588989). {ECO:0000269|PubMed:12482967, CC ECO:0000269|PubMed:14960582, ECO:0000269|PubMed:15004007, CC ECO:0000269|PubMed:15082531, ECO:0000269|PubMed:15764709, CC ECO:0000269|PubMed:20061393, ECO:0000269|PubMed:20118921, CC ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21454679, CC ECO:0000269|PubMed:25512613, ECO:0000269|PubMed:26588989}. 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:0000269|PubMed:26588989}; 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; CC Evidence={ECO:0000250|UniProtKB:O54949}; 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). CC {ECO:0000250|UniProtKB:O54949, ECO:0000269|PubMed:15082531, CC ECO:0000269|PubMed:15764709, ECO:0000269|PubMed:16714285, CC ECO:0000269|PubMed:20061393, ECO:0000269|PubMed:20118921, CC ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21454679, CC 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|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-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. {ECO:0000250|UniProtKB:O54949}. CC -!- PTM: Phosphorylated on Thr-298. Intermolecular autophosphorylation on CC Thr-298 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}. 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}; 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; 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; 67. 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 CPTAC; CPTAC-2835; -. DR CPTAC; CPTAC-2964; -. DR EPD; Q9UBE8; -. DR jPOST; Q9UBE8; -. DR MassIVE; Q9UBE8; -. DR PaxDb; 9606-ENSP00000384625; -. DR PeptideAtlas; Q9UBE8; -. DR ProteomicsDB; 83953; -. DR Antibodypedia; 13947; 419 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 AGR; HGNC:29858; -. 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; QNMTHEV; -. DR OrthoDB; 158564at2759; -. 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; 18 hits in 1192 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 189 other cell types or tissues. DR ExpressionAtlas; Q9UBE8; baseline and differential. 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; IDA:UniProtKB. DR GO; GO:0042169; F:SH2 domain binding; ISS:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0071470; P:cellular response to osmotic stress; IDA:UniProt. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IDA: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:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; 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 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. DR Genevisible; Q9UBE8; HS. 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|UniProtKB:O54949" 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|UniProtKB:O54949" FT REGION 434..527 FT /note="Required for interaction with TAB2" FT /evidence="ECO:0000250|UniProtKB:O54949" 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 //