ID NLK_MOUSE Reviewed; 527 AA. AC O54949; Q5SYE6; Q6PF98; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 03-NOV-2009, sequence version 2. DT 27-MAR-2024, entry version 179. DE RecName: Full=Serine/threonine-protein kinase NLK; DE EC=2.7.11.24 {ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:17785444}; DE AltName: Full=Nemo-like kinase; GN Name=Nlk {ECO:0000312|EMBL:AAC24499.1}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] {ECO:0000305, ECO:0000312|EMBL:AAC24499.1} RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ACTIVITY REGULATION, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF RP LYS-167 AND THR-298. RC STRAIN=BALB/cJ {ECO:0000312|EMBL:AAC24499.1}; RC TISSUE=Brain {ECO:0000312|EMBL:AAC24499.1}; RX PubMed=9448268; DOI=10.1073/pnas.95.3.963; RA Brott B.K., Pinsky B.A., Erikson R.L.; RT "Nlk is a murine protein kinase related to Erk/MAP kinases and localized in RT the nucleus."; RL Proc. Natl. Acad. Sci. U.S.A. 95:963-968(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Kidney; 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 [4] RP FUNCTION, AUTOPHOSPHORYLATION, ACTIVITY REGULATION, AND MUTAGENESIS OF RP LYS-167 AND CYS-437. RX PubMed=10391247; DOI=10.1038/21674; RA Ishitani T., Ninomiya-Tsuji J., Nagai S., Nishita M., Meneghini M., RA Barker N., Waterman M., Bowerman B., Clevers H., Shibuya H., Matsumoto K.; RT "The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta- RT catenin and transcription factor TCF."; RL Nature 399:798-802(1999). RN [5] {ECO:0000305} RP FUNCTION. RX PubMed=11745377; RX DOI=10.1002/1521-4141(200112)31:12<3580::aid-immu3580>3.0.co;2-n; RA Kortenjann M., Nehls M., Smith A.J., Carsetti R., Schuler J., Kohler G., RA Boehm T.; RT "Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk."; RL Eur. J. Immunol. 31:3580-3587(2001). 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, INTERACTION WITH LEF1 AND TCF7L2, AND MUTAGENESIS OF LYS-167. RX PubMed=12556497; DOI=10.1128/mcb.23.4.1379-1389.2003; RA Ishitani T., Ninomiya-Tsuji J., Matsumoto K.; RT "Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen- RT activated protein kinase-related Nemo-like kinase-dependent phosphorylation RT in Wnt/beta-catenin signaling."; RL Mol. Cell. Biol. 23:1379-1389(2003). RN [8] {ECO:0000305} RP FUNCTION. RX PubMed=14720327; DOI=10.1111/j.1349-7006.2004.tb03170.x; RA Yasuda J., Yokoo H., Yamada T., Kitabayashi I., Sekiya T., Ichikawa H.; RT "Nemo-like kinase suppresses a wide range of transcription factors, RT including nuclear factor-kappaB."; RL Cancer Sci. 95:52-57(2004). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH STAT3. 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 [10] {ECO:0000305} RP FUNCTION, INTERACTION WITH MYB AND HIPK2, AND MUTAGENESIS OF LYS-167 AND RP THR-298. 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 [11] RP FUNCTION, AND INTERACTION WITH MYB. RX PubMed=15308626; DOI=10.1074/jbc.m407831200; RA Kanei-Ishii C., Nomura T., Tanikawa J., Ichikawa-Iwata E., Ishii S.; RT "Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein RT degradation."; RL J. Biol. Chem. 279:44582-44589(2004). RN [12] RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH MYBL1 AND MYBL2, AND RP MUTAGENESIS OF LYS-167. RX PubMed=16055500; DOI=10.1091/mbc.e05-05-0470; RA Kurahashi T., Nomura T., Kanei-Ishii C., Shinkai Y., Ishii S.; RT "The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the RT association with coactivator CBP and methylating histone H3."; RL Mol. Biol. Cell 16:4705-4713(2005). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MEF2A. RX PubMed=17785444; DOI=10.1128/mcb.01481-07; RA Satoh K., Ohnishi J., Sato A., Takeyama M., Iemura S., Natsume T., RA Shibuya H.; RT "Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior RT formation in Xenopus development."; RL Mol. Cell. Biol. 27:7623-7630(2007). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain cortex; RX PubMed=17114649; DOI=10.1074/mcp.m600046-mcp200; RA Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., RA Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., RA Panse C., Schlapbach R., Mansuy I.M.; RT "Qualitative and quantitative analyses of protein phosphorylation in naive RT and stimulated mouse synaptosomal preparations."; RL Mol. Cell. Proteomics 6:283-293(2007). RN [15] RP FUNCTION, AND INTERACTION WITH E3 UBIQUITIN-PROTEIN LIGASE COMPLEXES. RX PubMed=18765672; DOI=10.1074/jbc.m804340200; RA Kanei-Ishii C., Nomura T., Takagi T., Watanabe N., Nakayama K.I., Ishii S.; RT "Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for nemo-like RT kinase (NLK)-induced degradation."; RL J. Biol. Chem. 283:30540-30548(2008). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-298, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Kidney, Liver, and Lung; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [17] RP FUNCTION, AUTOPHOSPHORYLATION, INTERACTION WITH MAP3K7 AND TAB2, AND RP MUTAGENESIS OF LYS-167. RX PubMed=20194509; DOI=10.1074/jbc.m109.083246; RA Li M., Wang H., Huang T., Wang J., Ding Y., Li Z., Zhang J., Li L.; RT "TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling."; RL J. Biol. Chem. 285:13397-13404(2010). RN [18] RP FUNCTION, INTERACTION WITH NOTCH1, AND MUTAGENESIS OF LYS-167. 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 [19] RP FUNCTION, AND INTERACTION WITH 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 [20] RP FUNCTION, AUTOPHOSPHORYLATION, ACTIVITY REGULATION, HOMODIMERIZATION, RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-298, AND MUTAGENESIS OF RP LYS-167; THR-298 AND CYS-437. RX PubMed=21118996; DOI=10.1091/mbc.e10-07-0605; RA Ishitani S., Inaba K., Matsumoto K., Ishitani T.; RT "Homodimerization of Nemo-like kinase is essential for activation and RT nuclear localization."; RL Mol. Biol. Cell 22:266-277(2011). CC -!- FUNCTION: Serine/threonine-protein kinase that regulates a number of CC transcription factors with key roles in cell fate determination CC (PubMed:10391247, PubMed:11745377, PubMed:12482967, PubMed:12556497, CC PubMed:14720327, PubMed:15004007, PubMed:17785444, PubMed:18765672, CC PubMed:20874444, PubMed:21118996, PubMed:9448268). Positive effector of CC the non-canonical Wnt signaling pathway, acting downstream of WNT5A, CC MAP3K7/TAK1 and HIPK2 (PubMed:15004007). Negative regulator of the CC canonical Wnt/beta-catenin signaling pathway (PubMed:20194509). Binds CC to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation CC of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the CC ubiquitination and subsequent proteolysis of LEF1 (PubMed:12556497). CC Together these effects inhibit the transcriptional activation of CC canonical Wnt/beta-catenin target genes (PubMed:12556497). Negative CC regulator of the Notch signaling pathway (PubMed:20118921). Binds to CC and phosphorylates NOTCH1, thereby preventing the formation of a CC transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and CC MAML1 (PubMed:20118921). Negative regulator of the MYB family of CC transcription factors (PubMed:16055500). Phosphorylation of MYB leads CC to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 CC inhibits their interaction with the coactivator CREBBP CC (PubMed:15082531, PubMed:15308626, PubMed:16055500). Other CC transcription factors may also be inhibited by direct phosphorylation CC of CREBBP itself (PubMed:15082531, PubMed:15308626, PubMed:16055500). CC Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is CC in turn required for activation of NLK by MAP3K7/TAK1 CC (PubMed:15004007). Upon IL1B stimulus, cooperates with ATF5 to activate CC the transactivation activity of C/EBP subfamily members (By CC similarity). Phosphorylates ATF5 but also stabilizes ATF5 protein CC levels in a kinase-independent manner (By similarity). Acts as an CC inhibitor of the mTORC1 complex in response to osmotic stress by CC mediating phosphorylation of RPTOR, thereby preventing recruitment of CC the mTORC1 complex to lysosomes (By similarity). CC {ECO:0000250|UniProtKB:Q9UBE8, ECO:0000269|PubMed:10391247, CC ECO:0000269|PubMed:11745377, ECO:0000269|PubMed:12482967, CC ECO:0000269|PubMed:12556497, ECO:0000269|PubMed:14720327, CC ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:15082531, CC ECO:0000269|PubMed:15308626, ECO:0000269|PubMed:16055500, CC ECO:0000269|PubMed:17785444, ECO:0000269|PubMed:18765672, CC ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20194509, CC ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21118996, CC ECO:0000269|PubMed:9448268}. 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:15004007, ECO:0000269|PubMed:17785444}; 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:0000269|PubMed:15004007, CC ECO:0000269|PubMed:17785444}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; 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. {ECO:0000269|PubMed:10391247, ECO:0000269|PubMed:12482967, CC ECO:0000269|PubMed:16055500, ECO:0000269|PubMed:21118996, CC ECO:0000269|PubMed:9448268}. CC -!- SUBUNIT: Homodimer. Homodimerization is required for intermolecular CC autophosphorylation, kinase activation and nuclear localization CC (PubMed:21118996). Interacts with RNF138/NARF (By similarity). CC Interacts with FOXO1 and FOXO3 (By similarity). Interacts with the CC upstream activating kinases HIPK2 and MAP3K7/TAK1. Interaction with CC MAP3K7/TAK1 seems to be indirect, and may be mediated by other proteins CC such as STAT3, TAB1 and TAB2. Interacts with and phosphorylates a CC number of transcription factors including FOXO4, LEF1, MYB, MYBL1, CC MYBL2, NOTCH1 and TCF7L2/TCF4. May interact with components of cullin- CC RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase CC complexes. Interacts with MEF2A (PubMed:12556497, PubMed:15004007, CC PubMed:15082531, PubMed:15308626, PubMed:16055500, PubMed:17785444, CC PubMed:18765672, PubMed:20118921, PubMed:20194509, PubMed:20874444). CC Interacts with ATF5; the interaction stabilizes ATF5 at the protein CC level in a kinase-independent manner (By similarity). CC {ECO:0000250|UniProtKB:Q9UBE8, ECO:0000269|PubMed:12556497, CC ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:15082531, CC ECO:0000269|PubMed:15308626, ECO:0000269|PubMed:16055500, CC ECO:0000269|PubMed:17785444, ECO:0000269|PubMed:18765672, CC ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20194509, CC ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21118996}. CC -!- INTERACTION: CC O54949; Q9QZR5: Hipk2; NbExp=2; IntAct=EBI-366894, EBI-366905; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21118996, CC ECO:0000269|PubMed:9448268}. Cytoplasm {ECO:0000269|PubMed:21118996}. CC Note=Predominantly nuclear. A smaller fraction is cytoplasmic. CC {ECO:0000269|PubMed:21118996}. CC -!- TISSUE SPECIFICITY: Expressed at high levels in the brain, and at lower CC levels in heart, kidney, lung and liver. {ECO:0000269|PubMed:9448268}. 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:0000269|PubMed:15082531, CC ECO:0000269|PubMed:21118996, ECO:0000269|PubMed:9448268}. CC -!- PTM: Phosphorylated on Thr-298. Intermolecular autophosphorylation on CC Thr-298 activates the enzyme. {ECO:0000269|PubMed:21118996}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. MAP kinase subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC24499.1; 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; AF036332; AAC24499.1; ALT_INIT; mRNA. DR EMBL; AL591177; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL591376; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC057667; AAH57667.2; -; mRNA. DR EMBL; BC058652; AAH58652.2; -; mRNA. DR CCDS; CCDS25113.2; -. DR RefSeq; NP_032728.3; NM_008702.3. DR AlphaFoldDB; O54949; -. DR SMR; O54949; -. DR BioGRID; 201785; 1. DR IntAct; O54949; 2. DR STRING; 10090.ENSMUSP00000119345; -. DR GlyGen; O54949; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O54949; -. DR PhosphoSitePlus; O54949; -. DR EPD; O54949; -. DR MaxQB; O54949; -. DR PaxDb; 10090-ENSMUSP00000119345; -. DR ProteomicsDB; 293576; -. DR Pumba; O54949; -. DR Antibodypedia; 13947; 419 antibodies from 37 providers. DR DNASU; 18099; -. DR Ensembl; ENSMUST00000142739.8; ENSMUSP00000119345.2; ENSMUSG00000017376.16. DR GeneID; 18099; -. DR KEGG; mmu:18099; -. DR UCSC; uc007kjw.1; mouse. DR AGR; MGI:1201387; -. DR CTD; 51701; -. DR MGI; MGI:1201387; Nlk. DR VEuPathDB; HostDB:ENSMUSG00000017376; -. DR eggNOG; KOG0664; Eukaryota. DR GeneTree; ENSGT00940000158363; -. DR HOGENOM; CLU_000288_133_2_1; -. DR InParanoid; O54949; -. DR OMA; QNMTHEV; -. DR OrthoDB; 158564at2759; -. DR PhylomeDB; O54949; -. DR TreeFam; TF315210; -. DR Reactome; R-MMU-4086398; Ca2+ pathway. DR BioGRID-ORCS; 18099; 3 hits in 78 CRISPR screens. DR ChiTaRS; Nlk; mouse. DR PRO; PR:O54949; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; O54949; Protein. DR Bgee; ENSMUSG00000017376; Expressed in rostral migratory stream and 258 other cell types or tissues. DR ExpressionAtlas; O54949; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISS:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0004707; F:MAP kinase activity; IDA:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IDA:MGI. 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; IPI:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISS:UniProtKB. DR GO; GO:0071470; P:cellular response to osmotic stress; ISO:MGI. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; ISS:UniProtKB. DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0042501; P:serine phosphorylation of STAT protein; IDA:UniProtKB. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; 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. DR Genevisible; O54949; MM. 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_0000186337" 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:0000269|PubMed:20194509" FT REGION 1..125 FT /note="Sufficient for interaction with DAPK3" FT /evidence="ECO:0000250|UniProtKB:Q9UBE8" 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|UniProtKB:Q9UBE8" FT REGION 428..527 FT /note="Required for homodimerization and kinase activation FT and localization to the nucleus" FT /evidence="ECO:0000269|PubMed:21118996" FT REGION 434..527 FT /note="Required for interaction with TAB2" FT /evidence="ECO:0000269|PubMed:20194509" FT MOTIF 298..300 FT /note="TQE" FT /evidence="ECO:0000269|PubMed:15082531, FT ECO:0000269|PubMed:21118996, ECO:0000269|PubMed:9448268" 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:0000269|PubMed:21118996, FT ECO:0007744|PubMed:21183079" FT MOD_RES 522 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UBE8" FT MUTAGEN 167 FT /note="K->M: Abrogates kinase activity and FT autophosphorylation. Retains ability to homodimerize. FT Abrogates ability to induce ubiquitination and degradation FT of LEF1 and repress canonical Wnt/beta-catenin signaling. FT Abrogates ability to induce MYB degradation, and reduces FT ability to repress MYBL1 and MYBL2." FT /evidence="ECO:0000269|PubMed:10391247, FT ECO:0000269|PubMed:12556497, ECO:0000269|PubMed:15082531, FT ECO:0000269|PubMed:16055500, ECO:0000269|PubMed:20118921, FT ECO:0000269|PubMed:20194509, ECO:0000269|PubMed:21118996, FT ECO:0000269|PubMed:9448268" FT MUTAGEN 298 FT /note="T->D,E: Abrogates autophosphorylation." FT /evidence="ECO:0000269|PubMed:15082531, FT ECO:0000269|PubMed:21118996, ECO:0000269|PubMed:9448268" FT MUTAGEN 298 FT /note="T->V: Abrogates autophosphorylation. Retains ability FT to homodimerize. Abrogates ability to induce MYB FT degradation." FT /evidence="ECO:0000269|PubMed:15082531, FT ECO:0000269|PubMed:21118996, ECO:0000269|PubMed:9448268" FT MUTAGEN 437 FT /note="C->S: Retains kinase activity." FT /evidence="ECO:0000269|PubMed:10391247, FT ECO:0000269|PubMed:21118996" FT MUTAGEN 437 FT /note="C->Y: Abrogates homodimerization and intermolecular FT autophosphorylation, with consequent loss of kinase FT activity. Loss of nuclear localization." FT /evidence="ECO:0000269|PubMed:10391247, FT ECO:0000269|PubMed:21118996" FT CONFLICT 69 FT /note="S -> P (in Ref. 1; AAC24499)" FT /evidence="ECO:0000305" 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 //