NLK

Summary

NLK (nemo like kinase, HGNC:29858) is a protein-coding gene on chromosome 17q11.2, encoding Serine/threonine-protein kinase NLK (Q9UBE8). Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination.

Enables DNA-binding transcription factor binding activity; protein serine/threonine kinase activity; and ubiquitin protein ligase binding activity. Involved in several processes, including negative regulation of TORC1 signaling; protein stabilization; and transforming growth factor beta receptor signaling pathway. Predicted to be located in cytosol and nucleoplasm. Predicted to be active in cytoplasm and nucleus.

Source: NCBI Gene 51701 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 48 total
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016231

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29858
Approved symbol	NLK
Name	nemo like kinase
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000087095
Ensembl biotype	protein_coding
OMIM	609476
Entrez	51701

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000407008, ENST00000496808, ENST00000582037, ENST00000583517, ENST00000584188, ENST00000584878, ENST00000910811, ENST00000923558, ENST00000955373

RefSeq mRNA: 1 — MANE Select: NM_016231 NM_016231

CCDS: CCDS11224

Canonical transcript exons

ENST00000407008 — 11 exons

Exon	Start	End
ENSE00000705948	28168448	28168657
ENSE00000706000	28161160	28161266
ENSE00000706087	28132620	28132675
ENSE00000706090	28122603	28122732
ENSE00000904519	28191021	28191219
ENSE00001200723	28163543	28163628
ENSE00001428262	28042677	28043331
ENSE00001825320	28194582	28196381
ENSE00003564767	28172517	28172618
ENSE00003606198	28192120	28192213
ENSE00003618702	28185179	28185265

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8464 / max 1139.7572, expressed in 1814 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159983	12.3400	1795
159988	2.7652	1236
159984	0.6752	286
159985	0.6675	306
159990	0.5949	194
159986	0.4838	188
159987	0.1965	72
159989	0.1234	45

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.48	gold quality
endothelial cell	CL:0000115	98.87	gold quality
pigmented layer of retina	UBERON:0001782	98.16	gold quality
primary visual cortex	UBERON:0002436	96.93	gold quality
parietal lobe	UBERON:0001872	96.91	gold quality
superior frontal gyrus	UBERON:0002661	96.80	gold quality
occipital lobe	UBERON:0002021	96.60	gold quality
postcentral gyrus	UBERON:0002581	96.58	gold quality
entorhinal cortex	UBERON:0002728	96.32	gold quality
adrenal tissue	UBERON:0018303	95.54	gold quality
medial globus pallidus	UBERON:0002477	95.52	gold quality
prefrontal cortex	UBERON:0000451	95.28	gold quality
globus pallidus	UBERON:0001875	95.22	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.14	gold quality
frontal cortex	UBERON:0001870	94.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.80	gold quality
substantia nigra pars compacta	UBERON:0001965	94.42	gold quality
neocortex	UBERON:0001950	94.19	gold quality
right frontal lobe	UBERON:0002810	94.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.07	gold quality
corpus callosum	UBERON:0002336	94.00	gold quality
cerebral cortex	UBERON:0000956	93.79	gold quality
lateral globus pallidus	UBERON:0002476	93.58	gold quality
inferior vagus X ganglion	UBERON:0005363	93.32	gold quality
buccal mucosa cell	CL:0002336	92.90	gold quality
subthalamic nucleus	UBERON:0001906	92.75	gold quality
temporal lobe	UBERON:0001871	92.68	gold quality
right adrenal gland cortex	UBERON:0035827	92.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	6.43
E-ANND-3	yes	4.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, GATA6, MYBL1, NFKB, STAT3

miRNA regulators (miRDB)

297 targeting NLK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Literature-anchored findings (GeneRIF, showing 40)

• These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca(2+) pathway and antagonizes canonical Wnt/beta-catenin signaling. (PMID:12482967)
• These results suggest that NLK phosphorylation on these sites contributes to the down-regulation of LEF-1/TCF transcriptional activity. (PMID:12556497)
• The induction of wild-type NLK in DLD-1 human colon cancer cells caused suppression of cell growth whereas the kinase-negative mutant did not. (PMID:12901858)
• Nemo-like kinase is activated by Wnt (PMID:14960582)
• STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases (PMID:15764709)
• These results strongly suggest that unlike cytokine signaling, Tax-induced NFkappaB activation does not involve K63 polyubiquitination-mediated MAP3K activation. (PMID:17418100)
• Fbxw7, the F-box protein of an SCF complex, targets c-Myb for degradation in a Wnt-1- and NLK-dependent manner. (PMID:18765672)
• NLK expression is altered during prostate cancer progression and it is involved in regulation of AR signaling in these cells (PMID:19514049)
• threonine 9 (Thr9) and Serine 138 (Ser138) within the N-terminal Mad homology1 (MH1) domain of Smad4 could be phosphorylated by NLK (PMID:19690946)
• findings provide the first evidence that TAK1-NLK pathway is a novel regulator of FOXO1 (PMID:20061393)
• NLK negatively regulates Notch-dependent transcriptional activation by phosphorylating Notch1ICD. Phosphorylated Notch1ICD is impaired in its ability to form a transcriptionally active ternary complex. (PMID:20118921)
• NLK is aberrantly regulated in hepatocellular carcinoma and this process appears to involve the induction of CDK2 and cyclin D1 (PMID:20512928)
• dimerization is an initial key event required for the functional activation of NLK (PMID:21118996)
• NLK induces apoptosis in glioma cells via activation of caspases; NLK may be a useful independent prognostic indicator for glioma. (PMID:21177110)
• ZIPK may serve as a transcriptional regulator of canonical Wnt/beta-catenin signaling through interaction with NLK/TCF4. (PMID:21454679)
• expression suppressed in the development of ovarian cancer (PMID:22027747)
• Single nucleotide polymorphisms in NLK is associated with ovarian cancer. (PMID:22253297)
• Our results suggested that NLK is a key regulator involved in proliferation and migration of GBC, and it could be used as a potential therapeutic target for gallbladder carcinoma cells. (PMID:22733362)
• Reduced expression of NLK is associated with glioma. (PMID:23416699)
• Data indicate that overexpression of nemo-like kinase (NLK) is closely related to progression of gallbladder cancer (GBC), and NLK could be used as a potential prognostic marker for GBC patients. (PMID:23857283)
• NLK is a negative regulator in cell proliferation of non-small-cell lung cancer by modulating the activity of Wnt/beta-catenin signaling. (PMID:23904219)
• NLK suppressed proliferation, induced apoptosis and mediated c-Myb degradation in MCF-7 cells. (PMID:23935942)
• The results suggest that NLK silencing by lentivirus-mediated RNA interference would be a potential therapeutic method to control oral squamous carcinoma growth. (PMID:23983589)
• High nemo-like kinase expression is associated with drug resistance in laryngeal cancer. (PMID:24460265)
• NLK functions as a pivotal negative regulator of NF-kappaB via disrupting the interaction of TAK1 with IKKbeta. (PMID:24721172)
• Data indicate that heat-shock protein 27 HSP27) binds to Nemo-like kinase (NLK) in the nucleus. (PMID:24816797)
• NLK is an important p53 regulator that responds to DNA damage. NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. (PMID:24926618)
• NLK was an identified miR-199a-3p target gene and functioned as a tumor suppressor gene in colorectal cancer. (PMID:24972723)
• the TAK1-NLK pathway is a novel regulator of basal or IL-1beta-triggered C/EBP activation though stabilization of ATF5 (PMID:25512613)
• our work first demonstrated that miR-197 can confer drug resistance to Taxol, by regulating tumor suppressor, NLK expression in ovarian cancer cells. (PMID:25833695)
• NLK overexpression is associated with poor overall survival in patients with hepatocellular carcinoma(HCC), it might be an independent poor prognostic marker for HCC. (PMID:26022162)
• Down-regulation of NLK inhibited tumorigenesis and up-regulated the expression of cell cycle proteins in laryngeal cancer cells. (PMID:26252054)
• NLK overexpression is an independent prognostic factor in colorectal cancer and knockdown of NLK expression inhibits colorectal cancer progression and metastasis. (PMID:26269673)
• In this review, we will make a summary on the comprehensive roles of NLK in the regulation of various cancers (PMID:26427665)
• Data show that metformin inhibits nemo like kinase (NLK) expression and might be a potential treatment strategy for non-small cell lung cancer (NSCLC). (PMID:26503334)
• NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. (PMID:26588989)
• Further experiments demonstrated that the overexpression of miR3623p resulted in decrease expression levels of nemo-like kinase (PMID:26647877)
• The expression of NLK was negatively correlated with TCF4 expression in lung cancers (PMID:26823848)
• NLK is a novel signaling molecule for proper lung development through the interconnection between epithelial and endothelial cells during lung morphogenesis (PMID:27035511)
• Our results suggest that NLK inhibits transcriptional activation of Nurr1 gene by impeding CBP’s role as a co-activator of NF-kappaB and CREB in prostate cancer. (PMID:27036119)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlk2	ENSDARG00000028793
mus_musculus	Nlk	ENSMUSG00000017376
rattus_norvegicus	Nlkl1	ENSRNOG00000066175
rattus_norvegicus		ENSRNOG00000071257
drosophila_melanogaster	nmo	FBGN0011817
drosophila_melanogaster	CG8565	FBGN0030697
drosophila_melanogaster	SRPK	FBGN0286813
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00003048
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
caenorhabditis_elegans		WBGENE00004980
caenorhabditis_elegans	gskl-2	WBGENE00007977
caenorhabditis_elegans	Y106G6E.1	WBGENE00013705

Paralogs (19): MAPK9 (ENSG00000050748), MAPK6 (ENSG00000069956), MOK (ENSG00000080823), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Serine/threonine-protein kinase NLK — Q9UBE8 (reviewed: Q9UBE8)

Alternative names: Nemo-like kinase, Protein LAK1

All UniProt accessions (3): Q9UBE8, H0YD75, J3QSE9

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Negative regulator of the canonical Wnt/beta-catenin signaling pathway. Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1. Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner. Acts as an inhibitor of the mTORC1 complex in response to osmotic stress by mediating phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1 complex to lysosomes.

Subunit / interactions. Homodimer. Homodimerization is required for intermolecular autophosphorylation, kinase activation and nuclear localization. May interact with components of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes. Interacts with LEF1, MEF2A, MYBL1 and MYBL2. Interacts with the upstream activating kinases HIPK2 and MAP3K7/TAK1. Interaction with MAP3K7/TAK1 seems to be indirect, and may be mediated by other proteins such as STAT3, TAB1 and TAB2. Interacts with and phosphorylates a number of transcription factors including FOXO1, FOXO3, FOXO4, MYB, NOTCH1 and TCF7L2/TCF4. Interacts with DAPK3/ZIPK, and this interaction may disrupt interaction with transcription factors such as TCF7L2/TCF4. Interacts with RNF138/NARF. Interacts with ATF5; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme.

Activity regulation. Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298. Activated by the non-canonical Wnt signaling pathway, in which WNT5A treatment leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Other cytokines such as IL6 may also activate this regulatory circuit.

Domain organisation. Contains a TQE activation loop motif in which autophosphorylation of the threonine residue (Thr-298) is sufficient for kinase activation. This mode of activation contrasts with that of classical MAP kinases, which contain a TXY activation loop motif in which phosphorylation of both the threonine and tyrosine residues is required for kinase activation.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

RefSeq proteins (1): NP_057315* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003527	MAP_kinase_CS	Conserved_site
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050117	MAPK	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (22 total): region of interest 7, compositionally biased region 3, binding site 2, modified residue 2, sequence variant 2, chain 1, domain 1, active site 1, mutagenesis site 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBE8-F1	76.46	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 264 (proton acceptor)

Ligand- & substrate-binding residues (2): 144–152; 167

Post-translational modifications (2): 298, 522

Mutagenesis-validated functional residues (1):

Position	Phenotype
167	abrogates kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-4086398	Ca2+ pathway

MSigDB gene sets: 431 (showing top): RNGTGGGC_UNKNOWN, CREL_01, AP1_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, ZHAN_MULTIPLE_MYELOMA_PR_DN, DORSAM_HOXA9_TARGETS_UP, GCM_PTPRD, KEGG_MAPK_SIGNALING_PATHWAY, CMYB_01, SP3_Q3, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GCM_ZNF198, GTTAAAG_MIR302B, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, TACAATC_MIR508

GO Biological Process (20): regulation of DNA-templated transcription (GO:0006355), protein phosphorylation (GO:0006468), transforming growth factor beta receptor signaling pathway (GO:0007179), Wnt signaling pathway, calcium modulating pathway (GO:0007223), peptidyl-threonine phosphorylation (GO:0018107), negative regulation of Wnt signaling pathway (GO:0030178), intracellular signal transduction (GO:0035556), protein stabilization (GO:0050821), cellular response to osmotic stress (GO:0071470), negative regulation of TORC1 signaling (GO:1904262), positive regulation of receptor signaling pathway via STAT (GO:1904894), MAPK cascade (GO:0000165), signal transduction (GO:0007165), regulation of signal transduction (GO:0009966), Wnt signaling pathway (GO:0016055), cellular response to nutrient levels (GO:0031669), cellular response to stress (GO:0033554), TORC1 signaling (GO:0038202), protein localization to lysosome (GO:0061462), positive regulation of TORC1 signaling (GO:1904263)

GO Molecular Function (14): magnesium ion binding (GO:0000287), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), ubiquitin protein ligase binding (GO:0031625), SH2 domain binding (GO:0042169), protein serine kinase activity (GO:0106310), DNA-binding transcription factor binding (GO:0140297), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Beta-catenin independent WNT signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to stimulus	3
cellular anatomical structure	3
intracellular anatomical structure	2
signal transduction	2
TORC1 signaling	2
regulation of TORC1 signaling	2
protein kinase activity	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
non-canonical Wnt signaling pathway	1
protein phosphorylation	1
peptidyl-threonine modification	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
regulation of protein stability	1
response to osmotic stress	1
cellular response to chemical stress	1
cellular response to abiotic stimulus	1
negative regulation of TOR signaling	1
positive regulation of signal transduction	1
cell surface receptor signaling pathway via STAT	1
regulation of receptor signaling pathway via STAT	1
intracellular signaling cassette	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
cell surface receptor signaling pathway	1
response to nutrient levels	1
response to stress	1
TOR signaling	1

Protein interactions and networks

STRING

814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLK	LEF1	Q9UJU2	724
NLK	TCF7L2	Q9NQB0	688
NLK	RNF138	Q8WVD3	681
NLK	HNF4A	P41235	666
NLK	SETDB1	Q15047	612
NLK	CTNNB1	P35222	600
NLK	LRP5	O75197	575
NLK	DVL1	O14640	539
NLK	BTRC	Q9Y297	535
NLK	FOXO1	Q12778	534
NLK	WNT5A	P41221	526
NLK	USP4	Q13107	516
NLK	AXIN1	O15169	492
NLK	ATXN1	P54253	484
NLK	SMARCA4	P51532	477

IntAct

79 interactions, top by confidence:

A	B	Type	Score
NLK	GRN	psi-mi:“MI:0915”(physical association)	0.780
GRN	NLK	psi-mi:“MI:0915”(physical association)	0.780
NLK	SMAD4	psi-mi:“MI:0915”(physical association)	0.720
SMAD4	NLK	psi-mi:“MI:0915”(physical association)	0.720
NLK	SMAD4	psi-mi:“MI:0403”(colocalization)	0.720
ZHX3	NLK	psi-mi:“MI:0915”(physical association)	0.670
ATXN1	NLK	psi-mi:“MI:0915”(physical association)	0.670
MAPK12	MAPK13	psi-mi:“MI:0914”(association)	0.640
NLK	RCHY1	psi-mi:“MI:0915”(physical association)	0.630
RCHY1	NLK	psi-mi:“MI:0915”(physical association)	0.630
NLK	RCHY1	psi-mi:“MI:0403”(colocalization)	0.630
NLK	MAP3K7	psi-mi:“MI:0914”(association)	0.570
NLK	MAP3K7	psi-mi:“MI:2364”(proximity)	0.570
NLK	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
NLK	QRICH1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-6	NLK	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (112): NLK (Two-hybrid), NLK (Two-hybrid), NLK (Two-hybrid), QRICH1 (Two-hybrid), KRTAP4-2 (Two-hybrid), KRTAP10-3 (Two-hybrid), KRTAP5-6 (Two-hybrid), CREBBP (Biochemical Activity), NLK (Co-localization), NLK (Co-localization), NLK (Two-hybrid), NLK (Co-localization), NLK (Two-hybrid), NLK (Affinity Capture-MS), NLK (Affinity Capture-RNA)

ESM2 similar proteins: A0A8I5ZNK2, B1H3E1, D3ZSZ3, D4ABL6, D4AE59, E1BMN8, E2QWQ2, E9PV86, O54804, O54949, O70293, P15209, P24786, P33497, P43250, P43291, P43292, P46892, P49137, P49138, P85298, P97711, Q03351, Q0GGW5, Q15831, Q16644, Q3SYZ2, Q3UMW7, Q5N942, Q5XIS9, Q63604, Q66H84, Q6ZI44, Q75H77, Q75V57, Q7XKA8, Q7XQP4, Q7Y0B9, Q8BZ03, Q8CIW5

Diamond homologs: A1CAF0, A2ZAB5, A4IIW7, A4QXX4, A6ZQG7, A6ZZF6, A7TGR2, B0VXE8, B0VXL7, B0XXN8, B1H3E1, B5X564, B6A7Q3, C0RW22, D3ZSZ3, E1BMN8, E2QWQ2, F4ICB6, F4IRW0, F4JY37, G5EBT1, G5EDT6, O00444, O08815, O13945, O14019, O35280, O35495, O54949, O54988, O55092, O59763, O61661, O64812, O80888, O94921, P0C198, P0C5D6, P22211, P22987

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
NLK	up-regulates	STAT3	phosphorylation
NLK	down-regulates	NOTCH1	phosphorylation
FZD3	up-regulates	NLK	binding
NLK	down-regulates	TCF4	phosphorylation
NLK	“down-regulates quantity”	LEF1	phosphorylation
NLK	“down-regulates quantity”	TCF7L2	phosphorylation
NLK	“down-regulates activity”	RPTOR	phosphorylation
NLK	“up-regulates activity”	YAP1	phosphorylation
NLK	“up-regulates activity”	CREBBP	phosphorylation
NLK	“down-regulates activity”	MYB	phosphorylation
MAP3K7	up-regulates	NLK	phosphorylation
NLK	down-regulates	LEF1	phosphorylation
NLK	down-regulates	TCF7L2	phosphorylation
NLK	“form complex”	SETDB1/NLK/CHD7	binding
NLK	“down-regulates activity”	FOXO1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

48 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2877 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28048043:G:GT	donor_gain	1.0000
17:28048044:A:T	donor_gain	1.0000
17:28122602:GGTCA:G	acceptor_gain	1.0000
17:28122733:G:GG	donor_gain	1.0000
17:28132690:G:T	donor_gain	1.0000
17:28168444:CTAG:C	acceptor_loss	1.0000
17:28168445:TA:T	acceptor_loss	1.0000
17:28168447:GAT:G	acceptor_gain	1.0000
17:28168447:GATTT:G	acceptor_gain	1.0000
17:28168653:AGCAG:A	donor_loss	1.0000
17:28168654:GCAG:G	donor_gain	1.0000
17:28168656:AGG:A	donor_loss	1.0000
17:28168658:G:GC	donor_loss	1.0000
17:28168659:T:A	donor_loss	1.0000
17:28172515:A:AG	acceptor_gain	1.0000
17:28172515:AGTT:A	acceptor_gain	1.0000
17:28172515:AGTTG:A	acceptor_gain	1.0000
17:28172516:G:GC	acceptor_gain	1.0000
17:28172516:GTT:G	acceptor_gain	1.0000
17:28172516:GTTG:G	acceptor_gain	1.0000
17:28172516:GTTGG:G	acceptor_gain	1.0000
17:28172581:GCGC:G	donor_gain	1.0000
17:28185177:A:AG	acceptor_gain	1.0000
17:28185178:G:GG	acceptor_gain	1.0000
17:28185178:GCC:G	acceptor_gain	1.0000
17:28185262:TCCA:T	donor_gain	1.0000
17:28185263:CCA:C	donor_gain	1.0000
17:28185264:CA:C	donor_gain	1.0000
17:28185265:AG:A	donor_loss	1.0000
17:28185266:G:A	donor_loss	1.0000

AlphaMissense

3471 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28043304:T:A	I144N	1.000
17:28043306:G:A	G145R	1.000
17:28043306:G:C	G145R	1.000
17:28043307:G:A	G145E	1.000
17:28043307:G:T	G145V	1.000
17:28043312:G:A	G147R	1.000
17:28043312:G:C	G147R	1.000
17:28043313:G:A	G147E	1.000
17:28043313:G:C	G147A	1.000
17:28043313:G:T	G147V	1.000
17:28043316:C:A	A148D	1.000
17:28043318:T:A	F149I	1.000
17:28043318:T:C	F149L	1.000
17:28043318:T:G	F149V	1.000
17:28043319:T:C	F149S	1.000
17:28043319:T:G	F149C	1.000
17:28043320:T:A	F149L	1.000
17:28043320:T:G	F149L	1.000
17:28043321:G:A	G150S	1.000
17:28043321:G:C	G150R	1.000
17:28043321:G:T	G150C	1.000
17:28043322:G:A	G150D	1.000
17:28043322:G:T	G150V	1.000
17:28043325:T:A	V151D	1.000
17:28043328:T:A	V152D	1.000
17:28043330:T:A	W153R	1.000
17:28043330:T:C	W153R	1.000
17:28122604:T:C	S154P	1.000
17:28122608:T:A	V155E	1.000
17:28122614:A:G	D157G	1.000

dbSNP variants (sampled 300 via entrez): RS1000018096 (17:28146449 T>C), RS1000039716 (17:28099639 C>T), RS1000051167 (17:28163458 A>G), RS1000060068 (17:28125300 A>G), RS1000064847 (17:28202165 G>A), RS1000068975 (17:28063865 A>G), RS1000077627 (17:28099827 C>A,G), RS1000096325 (17:28203338 G>A), RS1000136782 (17:28052942 T>G), RS1000165236 (17:28073739 A>G,T), RS1000165961 (17:28167062 A>G), RS1000213896 (17:28127576 A>C), RS1000214161 (17:28164139 G>A), RS1000218378 (17:28121262 G>A), RS1000221474 (17:28128232 C>A)

Disease associations

OMIM: gene MIM:609476 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003804_6	Non-response to bupropion and depression	6.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5364 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 249,337 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL5416410	DASATINIB	4	655
CHEMBL939	GEFITINIB	4	117,814
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1090089	PAMAPIMOD	2	428
CHEMBL1090090	VX-702	2	1,045
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL3120215	OSI-027	2	1,854
CHEMBL1230122	R-1487	1	42
CHEMBL1614725	TAK-285	1	1,016
CHEMBL3545328	XL-019	1	715
CHEMBL494089	GSK-690693	1	2,061
CHEMBL574738	AST-487	1	451

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — nmo subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 25 [PMID: 17935989]	Inhibition	5.79	pIC50

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
BMS-354825	KD	27 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM

ChEMBL bioactivities

88 potent at pChembl≥5 of 88 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.91	Kd	1.232	nM	CHEMBL3752910
8.73	ED50	1.853	nM	CHEMBL3752910
8.60	Ki	2.512	nM	CHEMBL1964692
8.52	Kd	3	nM	CHEMBL400402
8.40	Ki	3.981	nM	CHEMBL272453
8.30	Ki	5.012	nM	CHEMBL2000335
8.30	Ki	5.012	nM	CHEMBL1968406
8.22	Kd	6	nM	R-1487
7.89	IC50	13	nM	CHEMBL5090394
7.79	Kd	16.07	nM	CHEMBL5653589
7.70	Ki	19.95	nM	CHEMBL213505
7.70	Ki	19.95	nM	CHEMBL1242373
7.62	Kd	24	nM	CHEMBL3688339
7.62	ED50	24.17	nM	CHEMBL5653589
7.60	Kd	25	nM	SB-203580
7.60	Ki	25.12	nM	CHEMBL1976220
7.57	Kd	27	nM	XL-019
7.55	Kd	28	nM	CHEMBL4575895
7.55	Kd	28	nM	SB-202190
7.54	Kd	29	nM	CHEMBL4585158
7.50	Ki	31.62	nM	CHEMBL1979093
7.46	Kd	35	nM	CHEMBL386051
7.40	Ki	39.81	nM	CHEMBL394790
7.39	IC50	41	nM	CHEMBL5276374
7.30	Ki	50.12	nM	CHEMBL1984363
7.26	IC50	55.5	nM	STAUROSPORINE
7.20	Ki	63.1	nM	CHEMBL262433
7.15	IC50	70.2	nM	STAUROSPORINE
7.11	IC50	77.8	nM	STAUROSPORINE
6.90	Ki	125.9	nM	CHEMBL1994693
6.80	Kd	160	nM	AST-487
6.80	Kd	160	nM	VX-702
6.77	Kd	170	nM	PAMAPIMOD
6.77	Kd	170	nM	FORETINIB
6.66	Kd	220	nM	STAUROSPORINE
6.60	IC50	250	nM	CHEMBL5090394
6.60	Ki	251.2	nM	CHEMBL231209
6.59	Kd	258	nM	DASATINIB
6.58	Kd	260	nM	DASATINIB
6.47	IC50	336	nM	CHEMBL4517408
6.46	Kd	350	nM	CHEMBL530635
6.40	Ki	398.1	nM	CHEMBL1969190
6.39	Kd	410	nM	CHEMBL311959
6.35	Kd	449	nM	CHEMBL3991933
6.32	Kd	480	nM	CHEMBL1241674
6.30	Ki	501.2	nM	CHEMBL1997349
6.28	Kd	520	nM	CHEMBL4443342
6.19	Kd	650	nM	CHEMBL4556662
6.19	Kd	640	nM	SORAFENIB
6.18	Kd	660	nM	CHEMBL4517424

PubChem BioAssay actives

63 with measured affinity, of 918 total; 44 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148871: Binding affinity to human NLK incubated for 45 mins by Kinobead based pull down assay	kd	0.0012	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0030	uM
6-(2,4-difluorophenoxy)-8-methyl-2-(oxan-4-ylamino)pyrido[2,3-d]pyrimidin-7-one	592374: Inhibition of NLK	kd	0.0060	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148871: Binding affinity to human NLK incubated for 45 mins by Kinobead based pull down assay	kd	0.0161	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0240	uM
4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine	435667: Binding constant for full-length NLK	kd	0.0250	uM
N-[4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]phenyl]pyrrolidine-2-carboxamide	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0270	uM
4-(3,4,5-trimethoxyanilino)quinoline-7-carbonitrile	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0280	uM
4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]phenol	435667: Binding constant for full-length NLK	kd	0.0280	uM
4-(3,4,5-trimethoxyanilino)quinoline-6-carbonitrile	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0290	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	625100: Binding constant for NLK kinase domain	kd	0.0350	uM
(7S)-2-(3,5-dimethoxy-4-methylphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide	1948225: Inhibition of human NLK preincubated with compound for 1 hrs followed by ATP/33P-ATP addition and measured after 2 hrs by radioactive filter-binding assay	ic50	0.0410	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715239: Inhibition of human NLK using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0555	uM
6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)pyridine-3-carboxamide	476305: Binding affinity to NLK	kd	0.1600	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435667: Binding constant for full-length NLK	kd	0.1600	uM
6-(2,4-difluorophenoxy)-2-(1,5-dihydroxypentan-3-ylamino)-8-methylpyrido[2,3-d]pyrimidin-7-one	476305: Binding affinity to NLK	kd	0.1700	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625100: Binding constant for NLK kinase domain	kd	0.1700	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(3-fluoro-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1895123: Inhibition of human NLK by radiometric PanQinase activity assay	ic50	0.2500	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2580	uM
1-[4-[4-methyl-5-(3,4,5-trimethoxyphenyl)-3-pyridinyl]phenyl]piperazine	1665336: Inhibition of NLK (unknown origin)	ic50	0.3360	uM
6-tert-butyl-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.3500	uM
6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.4100	uM
3-(2-methyl-1,3-benzoxazol-5-yl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-amine	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4490	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625100: Binding constant for NLK kinase domain	kd	0.4800	uM
6-bromo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.5200	uM
Sorafenib	435667: Binding constant for full-length NLK	kd	0.6400	uM
6-chloro-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.6500	uM
6-iodo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.6600	uM
6-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673300: Binding affinity to wild-type human full length NLK expressed in bacterial expression system by Kinomescan method	kd	0.6900	uM
7-methoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.7000	uM
Encorafenib	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.7320	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507650: Binding affinity to NLK	kd	0.7700	uM
N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.8160	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	435667: Binding constant for full-length NLK	kd	1.0000	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1992792: Inhibition of NLK (unknown origin)	ic50	1.0340	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.4820	uM
Bosutinib	625100: Binding constant for NLK kinase domain	kd	2.2000	uM
6-methoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	2.6000	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-methoxyphenyl]-3-[1-(1,3-thiazol-2-yl)ethyl]urea	625100: Binding constant for NLK kinase domain	kd	3.0000	uM
4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexane-1-carboxylic acid	1425090: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.3310	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	625100: Binding constant for NLK kinase domain	kd	3.4000	uM
Gefitinib	625100: Binding constant for NLK kinase domain	kd	4.2000	uM
Pazopanib	435667: Binding constant for full-length NLK	kd	4.4000	uM
N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638751: Binding affinity to biotinylated full length human NLK expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	6.2000	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	2
trichostatin A	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
cupric oxide	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	increases expression, affects cotreatment	1
Lead	increases expression	1
Phenobarbital	affects expression	1
Quercetin	decreases expression	1
Theophylline	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases expression	1
Silver Compounds	decreases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

204 unique, capped per target: 203 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1041162	Binding	Residual activity of NLK at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem
CHEMBL1964113	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: NLK	PubChem BioAssay data set

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YN	Abcam HeLa NLK KO	Cancer cell line	Female
CVCL_D8RE	Ubigene HCT 116 NLK KO	Cancer cell line	Male
CVCL_E0J5	Ubigene HeLa NLK KO	Cancer cell line	Female
CVCL_TA75	HAP1 NLK (-) 1	Cancer cell line	Male
CVCL_TA76	HAP1 NLK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.