NEK6

Summary

NEK6 (NIMA related kinase 6, HGNC:7749) is a protein-coding gene on chromosome 9q33.3, encoding Serine/threonine-protein kinase Nek6 (Q9HC98). Protein kinase which plays an important role in mitotic cell cycle progression.

The protein encoded by this gene is a kinase required for progression through the metaphase portion of mitosis. Inhibition of the encoded protein can lead to apoptosis. This protein also can enhance tumorigenesis by suppressing tumor cell senescence. Several transcript variants encoding a few different isoforms have been found for this gene.

Source: NCBI Gene 10783 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 65 total
• Druggable target: yes — 10 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7749
Approved symbol	NEK6
Name	NIMA related kinase 6
Location	9q33.3
Locus type	gene with protein product
Status	Approved
Aliases	SID6-1512
Ensembl gene	ENSG00000119408
Ensembl biotype	protein_coding
OMIM	604884
Entrez	10783

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 39 protein_coding

ENST00000320246, ENST00000373596, ENST00000373600, ENST00000373603, ENST00000394199, ENST00000422297, ENST00000423785, ENST00000425237, ENST00000444973, ENST00000447379, ENST00000454453, ENST00000539416, ENST00000540326, ENST00000545174, ENST00000546191, ENST00000875860, ENST00000875861, ENST00000875862, ENST00000875863, ENST00000875864, ENST00000875865, ENST00000875866, ENST00000875867, ENST00000875868, ENST00000875869, ENST00000875870, ENST00000875871, ENST00000875872, ENST00000875873, ENST00000875874, ENST00000875875, ENST00000875876, ENST00000875877, ENST00000921947, ENST00000972168, ENST00000972169, ENST00000972170, ENST00000972171, ENST00000972172

RefSeq mRNA: 7 — MANE Select: NM_014397 NM_001145001, NM_001166167, NM_001166168, NM_001166169, NM_001166170, NM_001166171, NM_014397

CCDS: CCDS48015, CCDS55338, CCDS55339, CCDS6854

Canonical transcript exons

ENST00000320246 — 10 exons

Exon	Start	End
ENSE00000726897	124321459	124321569
ENSE00000726899	124313923	124313985
ENSE00000726901	124312509	124312649
ENSE00001035954	124350837	124353307
ENSE00001593436	124347709	124347822
ENSE00001607749	124339571	124339665
ENSE00001950796	124257949	124258085
ENSE00003508858	124301936	124302054
ENSE00003784548	124326330	124326438
ENSE00003785801	124327338	124327445

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 95.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.1256 / max 328.6940, expressed in 1798 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98454	35.3578	1790
98460	5.0515	723
98458	4.3842	1445
98457	1.5742	961
98468	1.0051	236
98467	0.7270	202
98455	0.6000	384
98456	0.3990	197
98469	0.3714	147
98465	0.2187	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.36	gold quality
stromal cell of endometrium	CL:0002255	95.29	gold quality
ventricular zone	UBERON:0003053	94.64	gold quality
right lobe of liver	UBERON:0001114	93.41	gold quality
vermiform appendix	UBERON:0001154	91.98	gold quality
liver	UBERON:0002107	91.16	gold quality
ileal mucosa	UBERON:0000331	91.03	gold quality
cartilage tissue	UBERON:0002418	90.99	gold quality
gall bladder	UBERON:0002110	90.61	gold quality
pancreatic ductal cell	CL:0002079	90.45	gold quality
monocyte	CL:0000576	89.00	gold quality
leukocyte	CL:0000738	88.79	gold quality
bone marrow cell	CL:0002092	88.77	gold quality
rectum	UBERON:0001052	88.25	gold quality
caudate nucleus	UBERON:0001873	87.64	gold quality
ganglionic eminence	UBERON:0004023	87.57	gold quality
pigmented layer of retina	UBERON:0001782	87.33	gold quality
colonic epithelium	UBERON:0000397	86.90	gold quality
nucleus accumbens	UBERON:0001882	86.83	gold quality
smooth muscle tissue	UBERON:0001135	86.79	gold quality
anterior cingulate cortex	UBERON:0009835	86.76	gold quality
putamen	UBERON:0001874	86.65	gold quality
amygdala	UBERON:0001876	86.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.41	gold quality
tibial nerve	UBERON:0001323	86.23	gold quality
lymph node	UBERON:0000029	86.20	gold quality
caecum	UBERON:0001153	85.68	gold quality
blood	UBERON:0000178	85.37	gold quality
endothelial cell	CL:0000115	85.28	gold quality
right frontal lobe	UBERON:0002810	85.18	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	348.22
E-MTAB-6386	no	530.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

68 targeting NEK6, 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-6740-5P	100.00	65.64	932
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-4804-3P	99.65	67.78	866

Literature-anchored findings (GeneRIF, showing 35)

• Also includes phylogenetic analysis and tissue-specific RT-PCR of human NEK6 and NEK7. (PMID:11701951)
• Molecular basis for the substrate specificity (PMID:12023960)
• molecular cloning and characterization of Nek6 (PMID:12054534)
• Activated by Nercc1/NEK9; part of the mitotic casscade (PMID:12840024)
• Nek6 kinase is required for the metaphase-anaphase transition (PMID:14563848)
• we found that Pin1 could interact with Nek6, one of the human NIMA-related kinases (Neks). Significant correlations between Nek6 and Pin1 mRNA expression levels in 40 pairs of hepatocellular carcinoma cases. (PMID:16476580)
• Nek6 binds to Fe65 through its (267)PPLP(270) motif; the protein-protein interaction between Nek6 and Fe65 regulates their subcellular localization and cell apoptosis (PMID:17512906)
• These results suggest that Nek6 is a novel target of the DNA damage checkpoint and that the inhibition of Nek6 activity is required for proper cell cycle arrest in the G(2)/M phase upon DNA damage. (PMID:18728393)
• both Nek6 and Nek7 are activated in mitosis and that interfering with their activity by either depletion or expression of reduced-activity mutants leads to mitotic arrest and apoptosis (PMID:19414596)
• NEK6 is overexpressed in various human cancer tissues, and ectopic expression of NEK6 increases tumor promoter-induced transformation of JB6 Cl41 mouse epidermal cells. (PMID:20595392)
• Findings open new perspectives in the study of hNek6 role in cancer by analyzing its novel interactions in specific pathways in tumor cells, which may provide important implications for drug design and cancer therapy. (PMID:20873783)
• NEK6 expression is downregulated in both replicative and premature senscence of human cnacer cells, and the inhibition of Nek6 activity is important for the onset of cellular senescence. (PMID:21099361)
• the first low resolution 3D structure of hNek6 protein in solution (PMID:21320329)
• DYNLL/LC8 protein controls signal transduction through the Nek9/Nek6 signaling module by regulating Nek6 binding to Nek9. (PMID:21454704)
• These results suggest that the increased expression of Nek6 renders cancer cells resistant to premature senescence, and targeting Nek6 could be an efficient strategy for cancer treatment. (PMID:21539811)
• Nek9 is a Plk1-activated kinase that controls early centrosome separation through Nek6/7 and Eg5. (PMID:21642957)
• High Nek6 is associated with hepatic cell cancer. (PMID:21725899)
• Nek6 plays an important role in the premature senescence of cancer cells. (PMID:23416273)
• Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway. (PMID:24763737)
• NEK6 suppresses the cell growth arrest induced by TGFbeta. Mechanically, NEK6 blocks nuclear translocation of Smad4, which is essential for TGFbeta function. (PMID:25523445)
• Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG-TACC3 complex. (PMID:25940345)
• Overexpression of AURKA and NEK6 genes was significantly more pronounced in Ulcerative colitis patients with more extensive colon involvement (PMID:26259750)
• overexpression of PAK1, NEK6, AURKA, and AURKB genes in patients with Colorectal adenomatous polyp and colorectal cancer in the Turkish population. (PMID:26423403)
• We found that NEK6-mediated phosphorylation of TPP1 Ser255 in G2/M phase regulates the association between telomerase activity and TPP1. Furthermore, we found evidence that POT1 negatively regulates TPP1 phosphorylation because the level of Ser255 phosphorylation was elevated when telomeres were elongated by a POT1 mutant lacking its OB-fold domains (PMID:27396482)
• our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer (PMID:27899381)
• cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma, were analyzed. (PMID:28329684)
• Signaling cascade of the NIMA-related kinases (Neks) Nek6, Nek7, and Nek9 is required for the localization and function of two kinesins essential for cytokinesis, Mklp2 and Kif14 to properly coordinate cytokinesis. (PMID:28630147)
• High NEK6 expression is associated with Cluster Amplified Centrosomes in cancer. (PMID:28720575)
• our results imply that Nek6 plays a facilitating role in breast cancer cell proliferation (PMID:30153958)
• CircNEK6 promoted the progression of thyroid cancer through up-regulating FZD8 and activating Wnt signaling pathway by targeting miR-370-3p. (PMID:30207869)
• Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression. (PMID:31409757)
• NEK6 is an injury-responsive kinase cooperating with STAT3 in regulation of reactive astrogliosis. (PMID:34643969)
• Predictive Role of NEK6 in Prognosis and Immune Infiltration in Head and Neck Squamous Cell Carcinoma. (PMID:35898455)
• CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity. (PMID:35993441)
• NEK6 Regulates Redox Balance and DNA Damage Response in DU-145 Prostate Cancer Cells. (PMID:36672191)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nek6	ENSDARG00000037963
mus_musculus	Nek6	ENSMUSG00000026749
rattus_norvegicus	Nek6	ENSRNOG00000010897

Paralogs (8): NEK11 (ENSG00000114670), NEK2 (ENSG00000117650), NEK9 (ENSG00000119638), NEK3 (ENSG00000136098), NEK7 (ENSG00000151414), NEK8 (ENSG00000160602), NEK10 (ENSG00000163491), NEK5 (ENSG00000197168)

Protein

Protein identifiers

Serine/threonine-protein kinase Nek6 — Q9HC98 (reviewed: Q9HC98)

Alternative names: Never in mitosis A-related kinase 6, Protein kinase SID6-1512

All UniProt accessions (8): Q9HC98, Q5TBG1, Q5TBG2, Q5TBG4, Q5TBG7, Q5TBH0, Q5TBH1, Q5TBH2

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIRSR, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence. Phosphorylates EML4 at ‘Ser-144’, promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression.

Subunit / interactions. Interacts with STAT3 and RPS6KB1. Interacts with NEK9, predominantly in mitosis. Interacts with KIF11 (via C-terminus). Interacts with APBB1 (via WW domain). Interacts with ANKRA2, ATF4, ARHGAP33, CDC42, CIRSR, PRAM1, PTN, PRDX3, PIN1, RAD26L, RBBP6, RPS7 and TRIP4.

Subcellular location. Cytoplasm. Nucleus. Nucleus speckle. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle pole.

Tissue specificity. Ubiquitous, with highest expression in heart and skeletal muscle.

Post-translational modifications. Autophosphorylated. Phosphorylation at Ser-206 is required for its activation. Phosphorylated upon IR or UV-induced DNA damage. Phosphorylated by CHEK1 and CHEK2. Interaction with APBB1 down-regulates phosphorylation at Thr-210.

Activity regulation. Binding to NEK9 stimulates its activity by releasing the autoinhibitory function of Tyr-108.

Domain organisation. Displays an autoinhibited conformation: Tyr-108 side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix. The autoinhibitory conformation is released upon binding with NEK9.

Induction. Up-regulated during the M phase of cell cycle progression. Down-regulated in both replicative and premature senescence of cancer cells.

Similarity. Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9HC98-1	1	yes
Q9HC98-2	2
Q9HC98-3	3
Q9HC98-4	4

RefSeq proteins (7): NP_001138473, NP_001159639, NP_001159640, NP_001159641, NP_001159642, NP_001159643, NP_055212* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site

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 (20 total): modified residue 4, splice variant 3, mutagenesis site 3, region of interest 3, binding site 2, chain 1, domain 1, sequence conflict 1, active site 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC98-F1	84.02	0.60

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 (2): 172 (proton acceptor); 108 (autoinhibitory)

Ligand- & substrate-binding residues (2): 51–59; 74

Post-translational modifications (4): 202, 206, 210, 37

Mutagenesis-validated functional residues (3):

Position	Phenotype
74	loss of autophosphorylation and of kinase activity and induction of apoptosis; when associated with m-75.
75	loss of autophosphorylation and of kinase activity and induction of apoptosis; when associated with m-74.
108	increase in catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-2980767	Activation of NIMA Kinases NEK9, NEK6, NEK7
R-HSA-3301854	Nuclear Pore Complex (NPC) Disassembly
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-1640170	Cell Cycle
R-HSA-2980766	Nuclear Envelope Breakdown
R-HSA-68875	Mitotic Prophase
R-HSA-68877	Mitotic Prometaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic

MSigDB gene sets: 309 (showing top): GOBP_CHROMOSOME_ORGANIZATION, AP1_01, LU_IL4_SIGNALING, GOBP_MEMBRANE_DISASSEMBLY, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_CELL_CYCLE_PHASE_TRANSITION, RACCACAR_AML_Q6, GOBP_CELLULAR_SENESCENCE, HEIDENBLAD_AMPLICON_8Q24_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, COUP_01, EVI1_05

GO Biological Process (14): protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), mitotic spindle organization (GO:0007052), chromosome segregation (GO:0007059), mitotic nuclear membrane disassembly (GO:0007077), regulation of mitotic cell cycle (GO:0007346), peptidyl-serine phosphorylation (GO:0018105), regulation of mitotic metaphase/anaphase transition (GO:0030071), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), protein autophosphorylation (GO:0046777), spindle assembly (GO:0051225), cell division (GO:0051301), regulation of cellular senescence (GO:2000772), regulation of chromosome organization (GO:0033044)

GO Molecular Function (15): magnesium ion binding (GO:0000287), transcription corepressor binding (GO:0001222), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), kinesin binding (GO:0019894), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), protein serine kinase activity (GO:0106310), DNA-binding transcription factor binding (GO:0140297), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), microtubule (GO:0005874), nuclear speck (GO:0016607), protein-containing complex (GO:0032991), centriolar satellite (GO:0034451), centrosome (GO:0005813), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Nuclear Envelope Breakdown	2
M Phase	2
Mitotic Prometaphase	1
Mitotic Prophase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
mitotic cell cycle	3
spindle organization	2
protein phosphorylation	2
protein kinase activity	2
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
microtubule cytoskeleton organization involved in mitosis	1
cell cycle process	1
nuclear membrane disassembly	1
mitotic cell cycle process	1
regulation of cell cycle	1
peptidyl-serine modification	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of metaphase/anaphase transition of cell cycle	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
chromosome segregation	1
membraneless organelle assembly	1
cellular process	1
regulation of cellular process	1
cellular senescence	1
regulation of organelle organization	1
chromosome organization	1
metal ion binding	1
transcription coregulator binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
kinase binding	1
ubiquitin-like protein ligase binding	1
transcription factor binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1

Protein interactions and networks

STRING

1006 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEK6	RCC1L	Q96I51	830
NEK6	BICD2	Q8TD16	776
NEK6	DENND1A	Q8TEH3	728
NEK6	CRB2	Q5IJ48	667
NEK6	LHX2	P50458	654
NEK6	CSN2	P05814	636
NEK6	DENND1B	Q6P3S1	602
NEK6	LHX9	Q9NQ69	565
NEK6	KIF11	P52732	546
NEK6	ANKS3	Q6ZW76	538
NEK6	NEK4	P51957	529
NEK6	ANKS6	Q68DC2	523
NEK6	NEK9	Q8TD19	522
NEK6	RCC1	P18754	520
NEK6	ARHGAP33	O14559	502

IntAct

151 interactions, top by confidence:

A	B	Type	Score
NEK6	NEK9	psi-mi:“MI:0914”(association)	0.780
NEK6	NEK9	psi-mi:“MI:0915”(physical association)	0.780
IKZF3	NEK6	psi-mi:“MI:0915”(physical association)	0.740
NEK6	IKZF3	psi-mi:“MI:0915”(physical association)	0.740
NEK7	ANKS6	psi-mi:“MI:0914”(association)	0.730
TCF4	NEK6	psi-mi:“MI:0915”(physical association)	0.670
TRIM23	NEK6	psi-mi:“MI:0915”(physical association)	0.670
XIAP	NEK6	psi-mi:“MI:0915”(physical association)	0.670
INCA1	NEK6	psi-mi:“MI:0915”(physical association)	0.670
NEK6	XIAP	psi-mi:“MI:0915”(physical association)	0.670
NECAB2	NEK6	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	NEK6	psi-mi:“MI:0915”(physical association)	0.560
NEK6	TNK2	psi-mi:“MI:0915”(physical association)	0.560
TLE5	NEK6	psi-mi:“MI:0915”(physical association)	0.560
NEK6	IKZF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (214): NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), NEK6 (Two-hybrid), IKZF3 (Two-hybrid), HSD17B14 (Two-hybrid), NECAB2 (Two-hybrid), FAM208B (Two-hybrid), LZTS2 (Two-hybrid), LNX1 (Two-hybrid), KRT40 (Two-hybrid)

ESM2 similar proteins: A0A5B9GBF0, A1CPG7, A1D2C9, A1IVT7, A2BD05, A2QRF6, B0XR80, D3ZBE5, G1XJZ4, G5EDF7, G5EFM9, M1T7M3, O09110, O75716, O88697, P0CP69, P21708, P26696, P27361, P28482, P45985, P46196, P46734, P47809, P52564, P57760, P59895, P70236, Q0D0P5, Q0U4L8, Q1DUU8, Q1KTF2, Q2WFL5, Q4PC06, Q4W6D3, Q4WSF6, Q52PH6, Q56R42, Q5E9X2, Q63844

Diamond homologs: A0A078CGE6, A2BD05, A2QHV0, A2ZMH2, A7SNN5, D3ZBE5, D3ZGQ5, E9Q3S4, G5EFM9, H2L099, O01775, O13839, O14047, O22040, O22042, O35942, O61122, P11837, P22209, P41892, P48479, P48963, P51954, P51955, P51956, P51957, P59895, P84199, Q03428, Q08942, Q0CL79, Q0KHQ5, Q0WPH8, Q10GB1, Q2QAV0, Q2QMH1, Q3SWY6, Q3UGM2, Q40541, Q4FZD7

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
NEK9	“up-regulates activity”	NEK6	phosphorylation
NEK6	“up-regulates activity”	ACD	phosphorylation
NEK6	“down-regulates activity”	BSG	phosphorylation
NEK6	“up-regulates activity”	KIF11	phosphorylation
NEK6	“down-regulates activity”	KIF20A	phosphorylation
NEK6	“up-regulates activity”	STAT3	phosphorylation
NEK6	“up-regulates activity”	FOXJ2	phosphorylation
NEK6	“down-regulates activity”	EML4	phosphorylation
NEK6	“up-regulates activity”	SGK1	phosphorylation
NEK6	“up-regulates activity”	RPS6KB1	phosphorylation
NEK6	“up-regulates activity”	EML4	phosphorylation
NEK6	“up-regulates activity”	HSPA1A	phosphorylation
NEK6	“down-regulates activity”	NUP98	phosphorylation
NEK6	“up-regulates activity”	PSMD2	phosphorylation
CHEK1	“down-regulates activity”	NEK6	phosphorylation
CHEK2	“down-regulates activity”	NEK6	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2328 predictions. Top by Δscore:

Variant	Effect	Δscore
9:124312507:A:AG	acceptor_gain	1.0000
9:124312507:AGAG:A	acceptor_gain	1.0000
9:124312508:G:GG	acceptor_gain	1.0000
9:124312508:GA:G	acceptor_gain	1.0000
9:124312508:GAGG:G	acceptor_gain	1.0000
9:124312508:GAGGC:G	acceptor_gain	1.0000
9:124312543:T:A	acceptor_gain	1.0000
9:124312622:G:GT	donor_gain	1.0000
9:124312645:TGCAG:T	donor_loss	1.0000
9:124312648:AGGTG:A	donor_loss	1.0000
9:124312649:GGTGA:G	donor_loss	1.0000
9:124312651:T:G	donor_loss	1.0000
9:124313915:C:A	acceptor_loss	1.0000
9:124313915:C:CA	acceptor_gain	1.0000
9:124313919:CAAG:C	acceptor_loss	1.0000
9:124313920:A:AG	acceptor_gain	1.0000
9:124313920:AAG:A	acceptor_loss	1.0000
9:124313921:A:AT	acceptor_loss	1.0000
9:124313921:A:G	acceptor_gain	1.0000
9:124313922:G:A	acceptor_loss	1.0000
9:124313922:G:GC	acceptor_gain	1.0000
9:124313922:GA:G	acceptor_gain	1.0000
9:124313922:GAT:G	acceptor_gain	1.0000
9:124313922:GATC:G	acceptor_gain	1.0000
9:124313922:GATCT:G	acceptor_gain	1.0000
9:124313984:AGGTG:A	donor_loss	1.0000
9:124313985:GGT:G	donor_loss	1.0000
9:124313986:G:GA	donor_loss	1.0000
9:124313986:G:GG	donor_gain	1.0000
9:124313987:T:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000041159 (9:124328842 C>A), RS1000048696 (9:124310774 T>G), RS1000135275 (9:124320663 C>G), RS1000181137 (9:124342482 A>C), RS1000220895 (9:124305012 A>C), RS1000236085 (9:124272658 T>C), RS1000283174 (9:124342529 T>C,G), RS1000298385 (9:124315529 G>A,T), RS1000305463 (9:124288654 A>C,G), RS1000312011 (9:124279096 G>T), RS1000316289 (9:124263214 G>A,T), RS1000377276 (9:124310047 G>A,C), RS1000394459 (9:124273871 G>C,T), RS1000410206 (9:124258423 G>A), RS1000446852 (9:124293796 G>A,T)

Disease associations

OMIM: gene MIM:604884 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000579_1	Cognitive performance	3.000000e-06
GCST002927_8	Mercury levels	7.000000e-06
GCST004785_30	Vitiligo	1.000000e-08
GCST006629_73	Pulse pressure	7.000000e-12
GCST006896_15	Free thyroxine concentration	5.000000e-11
GCST006940_158	Neurociticism	5.000000e-08
GCST006979_551	Heel bone mineral density	9.000000e-14
GCST006988_101	Blond vs. brown/black hair color	5.000000e-14
GCST006988_11	Blond vs. brown/black hair color	1.000000e-16
GCST007100_8	Asthma exacerbations in inhaled corticosteroid treatment	4.000000e-06
GCST007576_433	Chronotype	1.000000e-09
GCST007932_94	Medication use (thyroid preparations)	5.000000e-09
GCST010042_45	Asthma	1.000000e-08
GCST010043_167	Asthma	2.000000e-12
GCST010653_68	Thyroid stimulating hormone levels	4.000000e-12

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0005763	pulse pressure measurement
EFO:0007660	neuroticism measurement
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0007614	asthma exacerbation measurement
EFO:0008328	chronotype measurement
EFO:0009933	Thyroid preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4309 (SINGLE PROTEIN), CHEMBL4524130 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

10 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 86,482 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL50	QUERCETIN	3	74,559
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL564829	MILCICLIB	2	821
CHEMBL575448	BMS-754807	2	406
CHEMBL1908397	KW-2449	1	622
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 — NIMA (never in mitosis gene a)- related kinase (NEK) family

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM

ChEMBL bioactivities

33 potent at pChembl≥5 of 40 total, top 27 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	Kd	6.3	nM	R-406
6.92	Kd	120	nM	KW-2449
6.92	Kd	120	nM	FEDRATINIB
6.89	Kd	130	nM	CHEMBL3763358
6.70	Kd	200	nM	BMS-754807
6.47	IC50	336	nM	CHEMBL1793896
6.28	IC50	520	nM	CHEMBL3104851
6.22	IC50	595	nM	CHEMBL1271644
6.22	Kd	600	nM	SU-014813
5.97	IC50	1065	nM	MILCICLIB
5.89	Kd	1300	nM	TAE-684
5.82	Kd	1500	nM	DOVITINIB
5.78	IC50	1664	nM	CHEMBL1272140
5.73	IC50	1850	nM	CHEMBL3104855
5.60	Kd	2500	nM	AST-487
5.58	IC50	2600	nM	CHEMBL4568087
5.58	IC50	2600	nM	CHEMBL4862849
5.48	IC50	3306	nM	CHEMBL4640297
5.47	IC50	3400	nM	CHEMBL4875865
5.37	IC50	4230	nM	QUERCETIN
5.36	Kd	4400	nM	LESTAURTINIB
5.27	IC50	5350	nM	CHEMBL4638981
5.23	IC50	5900	nM	CHEMBL4550702
5.22	IC50	6020	nM	CHEMBL1236095
5.11	IC50	7720	nM	CHEMBL3109404
5.06	IC50	8800	nM	CHEMBL4569508
5.00	IC50	1e+04	nM	CHEMBL3884319

PubChem BioAssay actives

31 with measured affinity, of 1199 total; 25 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
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	1948827: Inhibition of NEK6 (unknown origin) assessed as dissociation constant	kd	0.0063	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	1948827: Inhibition of NEK6 (unknown origin) assessed as dissociation constant	kd	0.1200	uM
Fedratinib	1948827: Inhibition of NEK6 (unknown origin) assessed as dissociation constant	kd	0.1200	uM
2-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yl]-5-pyridin-2-yl-1,2,4-triazol-3-amine	1276290: Binding affinity to human NEK6	kd	0.1300	uM
(2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methylpyrrolidine-2-carboxamide	2167400: Binding affinity to NEK6 (unknown origin) by phage based competition assay	kd	0.2000	uM
1-ethenyl-8-[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,5-h]quinazoline-3-carboxamide	528004: Inhibition of NEK6	ic50	0.3360	uM
(1S,9R)-5,6,12,13,14-pentahydroxy-4,11-dimethyl-16-oxo-8,17-dioxatetracyclo[7.7.1.02,7.010,15]heptadeca-2(7),3,5,10,12,14-hexaene-3-carbaldehyde	1063043: Inhibition of NEK6 (unknown origin)	ic50	0.5200	uM
1-methyl-8-[5-piperazin-1-yl-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,5-h]quinazoline-3-carboxamide	528004: Inhibition of NEK6	ic50	0.5950	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	625079: Binding constant for NEK6 kinase domain	kd	0.6000	uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide	422335: Inhibition of NEK6	ic50	1.0650	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625079: Binding constant for NEK6 kinase domain	kd	1.3000	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435545: Binding constant for NEK6 kinase domain	kd	1.5000	uM
1-methyl-8-[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,5-h]quinazoline-3-carboxamide	528004: Inhibition of NEK6	ic50	1.6640	uM
2-(2-formyl-3,4,5-trihydroxy-6-methylphenyl)-6,7-dihydroxy-5-methyl-1-benzofuran-4-carbaldehyde	1063043: Inhibition of NEK6 (unknown origin)	ic50	1.8500	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	1948827: Inhibition of NEK6 (unknown origin) assessed as dissociation constant	kd	2.5000	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637113: Inhibition of full-length recombinant human GST-tagged NEK6 expressed in insect cells by Z’-LYTE assay	ic50	2.6000	uM
N-[4-(1,3a,4,5,7,7a-hexahydropyrazolo[3,4-c]pyridin-6-ylmethyl)-3-chlorophenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648819: Inhibition of NEK6 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	3.3060	uM
Quercetin	1063043: Inhibition of NEK6 (unknown origin)	ic50	4.2300	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	625079: Binding constant for NEK6 kinase domain	kd	4.4000	uM
N-[3-chloro-4-(4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-5-ylmethyl)phenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648819: Inhibition of NEK6 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	5.3500	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637113: Inhibition of full-length recombinant human GST-tagged NEK6 expressed in insect cells by Z’-LYTE assay	ic50	5.9000	uM
N-(2,6-diethylphenyl)-1-methyl-8-[4-[(1-methylpiperidin-4-yl)carbamoyl]-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,5-h]quinazoline-3-carboxamide	2186312: Inhibition of recombinant NEK6 (unknown origin)	ic50	6.0200	uM
methyl 3-[[(1R,2S,4aR,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4,5-dihydroxybenzoate	1066601: Inhibition of recombinant NEK6 (unknown origin) assessed as incorporation of [gamma-33P]-ATP into substrate by radiometric assay	ic50	7.7200	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637113: Inhibition of full-length recombinant human GST-tagged NEK6 expressed in insect cells by Z’-LYTE assay	ic50	8.8000	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336080: Inhibition of human recombinant full length GST-tagged NEK6 expressed in insect expression system	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
bisphenol A	increases expression, increases methylation, affects expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects methylation, increases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	decreases methylation	1
gardiquimod	increases expression, decreases reaction	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1

ChEMBL screening assays

347 unique, capped per target: 346 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003309	Binding	Inhibition of NEK6 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL899292	Functional	Inhibition of NEK6 assessed as residual activity at 1 uM	Carbocyclic 3’-deoxyadenosine-based highly potent bisubstrate-analog inhibitor of basophilic protein kinases. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1YI	Abcam HeLa NEK6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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