NKX3-1

Summary

NKX3-1 (NK3 homeobox 1, HGNC:7838) is a protein-coding gene on chromosome 8p21.2, encoding Homeobox protein Nkx-3.1 (Q99801). Transcription factor, which binds preferentially the consensus sequence 5’-TAAGT[AG]-3’ and can behave as a transcriptional repressor.

This gene encodes a homeobox-containing transcription factor. This transcription factor functions as a negative regulator of epithelial cell growth in prostate tissue. Aberrant expression of this gene is associated with prostate tumor progression. Alternate splicing results in multiple transcript variants of this gene.

Source: NCBI Gene 4824 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 26 total
• Transcription factor: yes — 74 downstream targets (CollecTRI)
• MANE Select transcript: NM_006167

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7838
Approved symbol	NKX3-1
Name	NK3 homeobox 1
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	NKX3.1, BAPX2
Ensembl gene	ENSG00000167034
Ensembl biotype	protein_coding
OMIM	602041
Entrez	4824

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000380871, ENST00000523261

RefSeq mRNA: 2 — MANE Select: NM_006167 NM_001256339, NM_006167

CCDS: CCDS59095, CCDS6042

Canonical transcript exons

ENST00000380871 — 2 exons

Exon	Start	End
ENSE00001486608	23678697	23681639
ENSE00001486631	23682604	23682938

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 97.93.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8842 / max 120.7106, expressed in 694 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92339	2.8842	694

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	97.93	gold quality
secondary oocyte	CL:0000655	96.81	gold quality
sperm	CL:0000019	96.25	gold quality
male germ cell	CL:0000015	95.95	gold quality
prostate gland	UBERON:0002367	94.07	gold quality
trachea	UBERON:0003126	92.38	gold quality
oocyte	CL:0000023	92.04	gold quality
type B pancreatic cell	CL:0000169	90.60	gold quality
olfactory bulb	UBERON:0002264	90.44	gold quality
germinal epithelium of ovary	UBERON:0001304	87.61	gold quality
urethra	UBERON:0000057	86.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.13	gold quality
nasal cavity mucosa	UBERON:0001826	83.73	gold quality
minor salivary gland	UBERON:0001830	83.21	gold quality
nasal cavity epithelium	UBERON:0005384	83.02	gold quality
right testis	UBERON:0004534	82.49	gold quality
cartilage tissue	UBERON:0002418	82.28	gold quality
testis	UBERON:0000473	82.25	gold quality
left testis	UBERON:0004533	81.10	gold quality
saliva-secreting gland	UBERON:0001044	80.74	gold quality
mouth mucosa	UBERON:0003729	80.56	gold quality
mucosa of paranasal sinus	UBERON:0005030	80.05	gold quality
adult organism	UBERON:0007023	79.15	gold quality
pancreatic ductal cell	CL:0002079	78.53	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	77.72	gold quality
superior surface of tongue	UBERON:0007371	75.58	gold quality
tibialis anterior	UBERON:0001385	74.50	gold quality
epithelial cell of pancreas	CL:0000083	74.36	silver quality
buccal mucosa cell	CL:0002336	74.23	silver quality
islet of Langerhans	UBERON:0000006	73.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	8.53
E-CURD-10	no	620.34
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

74 targets.

Target	Regulation
ABCB1
ABL2
ACHE
ACTG2	Activation
AHR
AKT1
AR	Repression
B3GNT9
BAX	Activation
BCL2	Repression
BCL2L1
CASP3	Activation
CASP8
CASP9
CBX5
CCND1	Repression
CD44
CDKN1B
CHD1
CLIC4
CLU	Repression
CTSE	Repression
DKK3
ESR1	Unknown
FOS	Repression
GADD45A
HGF
IGF1R	Repression
IGFBP3	Activation
IGFBP6

JASPAR motifs

Motif	Name	Family
MA0124.1	NKX3-1	NK

JASPAR matrix evidence (PMIDs): PMID:10871372

Upstream regulators (CollecTRI, top): AR, ERG, ETS1, FOXO1, GATA3, HIF1A, LMO1, LYL1, MSX2, MYC, NKX3-1, PAX1, PITX1, SOX4, SP1, TAL1, TCF15, TP53

miRNA regulators (miRDB)

117 targeting NKX3-1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583

Literature-anchored findings (GeneRIF, showing 40)

• NKX-3.1 interacts with prostate-derived Ets factor and regulates the activity of the PSA promoter. (PMID:11809674)
• smooth muscle gamma actin gene activity in prostate epithelia is due, in part, to the androgen-dependent expression of Nkx 3.1 (PMID:12450213)
• Expression of NKX3.1 is highly restricted and is found primarily in benign and malignant prostatic epithelial cells and also in normal testis and lobular carcinoma of the breast. (PMID:12661036)
• NKX3.1 is essential for normal testis function and that its loss of expression is highly associated with the invasive phenotype of testicular germ cell tumors. (PMID:14633588)
• Nkx3.1 homeobox gene has roles in prostate organogenesis and carcinogenesis (review) (PMID:14648854)
• NKX3.1 does not function as a typical tumor suppressor protein in prostate cancer but it may still have important regulatory roles during prostate cancer progression (PMID:15311057)
• identified novel protein-protein interaction domains within NKX-3.1 and PDEF that operate in concert with their respective DNA binding domains to mediate functional interactions between these growth regulatory transcription factors (PMID:15523673)
• Down-regulation of NKX3.1 expression is not caused by promoter hypermethylation in testicular germ cell tumors and prostate carcinomas. (PMID:15691383)
• Even in the presence of allelic loss, NKX3.1 expression is reduced over a wide range in prostate cancer. (PMID:15734999)
• We found that the 20 bp inhibitory decoy could enhance NKX3.1 promoter activity, and RT-PCR and Western blot analysis revealed that NKX3.1 expression was up-regulated effectively by the transfection with the 20 bp inhibitory decoy. (PMID:15880262)
• Nkx3.1 negatively regulates Sp-mediated transcription via the tethering of histone deacetylases and/or by inhibiting the association of Sp proteins with co-activators. (PMID:16201967)
• Nkx3.1 and Egr1 regulate gene programs involved in distinct aspects of prostate tumorigenesis [review] (PMID:16382041)
• Germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper. (PMID:16397218)
• NKX3.1 expression is significantly decreased in prostate cancer patients but that was not correlated with prostate cancer progression and was not associated with advanced stage. Thus, NKX3.1 expression is not a clinically valuable prognostic factor. (PMID:16413692)
• NKX3.1 is not only the prostate-specific homeobox gene, but is the epithelia-cell specific gene of prostate. It may play an important role in the development of prostatic carcinoma. (PMID:16519150)
• NKX3-1 is regulated by protein kinase CK2 in prostate tumor cells. (PMID:16581776)
• PTEN loss causes reduced NKX3.1 expression in both murine and human prostate cancers. (PMID:16697957)
• Identifies two novel interaction motifs with SRF and one novel intra-protein interaction involving NKX3-1 homeodomain (PMID:16814806)
• These studies demonstrate that the NKX3.1 gene is a direct target of retinoid receptors and suggest that androgen regulation of NKX3.1 expression is mediated in part by the 3’untranslated region. (PMID:16817226)
• There is a functional inhibitory cis-element between -362 and -343 in the upstream of NKX3.1 gene, a prostate-specific homeobox gene related to prostate development and prostate cancer. It may play a role in downregulating NKX3.1 gene transcription. (PMID:16845664)
• Reduced NKX3.1 protein levels early in human prostate carcinogenesis may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with advanced invasive and aggressive disease. (PMID:17108105)
• NKX3.1 is down-regulated by p53 over-expression in prostate cancer cells (PMID:17202838)
• NKX3.1 interacts with Topo I to enhance formation of the Topo I-DNA complex and to increase Topo I cleavage of DNA. (PMID:17234752)
• The present study demonstrates that re-expression of Nkx3.1 enhances 17beta-estradiol anti-tumor action in PC3 human prostate cancer cells. (PMID:17486276)
• NKX3.1 can be ubiquitinated by TOPORS in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells (PMID:18077445)
• identified novel protein-protein interacting domains within Nkx3.1 and serum response factor (PMID:18296735)
• In LNCaP NKX3.1 most probably plays the role of an androgen-regulated transcription factor whose down-regulation is paralleled by anti-proliferative and pro-apoptotic effects. (PMID:18360715)
• These results suggested that two functional NKX3.1 binding sites located at -1848 to -1836 and -803 to -791 upstream of the PCAN1 gene were involved in the positive regulation of PCAN1 gene transcription by NKX3.1. (PMID:18454873)
• cellular levels of the NKX3.1 tumor suppressor are affected by inflammatory cytokines that target COOH-terminal serine residues to activate ubiquitination and protein degradation (PMID:18757402)
• regulation of VEGF-C expression by NKX3.1 provides a possible mechanism by which the loss of NKX3.1 protein level leads to lymphangiogenesis in the late stages of advanced prostate cancer (PMID:18974119)
• The growth-suppressive effects of NKX3.1 in prostate cells are mediated, in part, by activation of IGFBP-3 expression. (PMID:19258508)
• With deletion mutation analysis, plasmid construction, EMSA and oligonucleotide decoy technique, two Sp1-elements which located between +29 to +43 and -60 to -46 of NKX3.1 gene were identified and proven to be functional elements. (PMID:19263243)
• Nkx3.1 and p27(KIP1) cooperate in proliferation inhibition and apoptosis induction in human androgen-independent prostate cancer cells. (PMID:19266349)
• NKX3.1 might exert its function by regulating the expression of relative genes in prostate development and carcinogenesis. (PMID:19462257)
• NKX3.1 constructs with acidic domain phosphorylation site threonine residues (89 and 93) mutated to glutamate were 4 degrees C more stable than homeodomain alone (PMID:19780584)
• MYOCD can discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter (PMID:19797053)
• Androgen regulation of the prostatic tumour suppressor NKX3.1 is mediated by its 3’ untranslated region (PMID:19886863)
• Nkx3.1 has a role in bacterial prostatitis and its progression to inflammation and neoplasia (PMID:20363913)
• NKX3.1 activates cellular response to DNA damage (PMID:20395202)
• The prostate-specific tumor suppressor gene Nkx3.1 was controlled by ERG and ESE3 both directly and through induction of EZH2. (PMID:20479932)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	nkx3-1	ENSDARG00000078280
mus_musculus	Nkx3-1	ENSMUSG00000022061
rattus_norvegicus	Nkx3-1	ENSRNOG00000015477
drosophila_melanogaster	NK7.1	FBGN0024321
drosophila_melanogaster	HGTX	FBGN0040318
drosophila_melanogaster	scro	FBGN0287186
caenorhabditis_elegans	ceh-9	WBGENE00000434
caenorhabditis_elegans		WBGENE00000447
caenorhabditis_elegans		WBGENE00000450
caenorhabditis_elegans		WBGENE00000584

Paralogs (13): NKX3-2 (ENSG00000109705), NKX2-3 (ENSG00000119919), NKX2-4 (ENSG00000125816), NKX2-2 (ENSG00000125820), NKX2-8 (ENSG00000136327), NKX2-1 (ENSG00000136352), NKX6-2 (ENSG00000148826), NKX6-1 (ENSG00000163623), NKX6-3 (ENSG00000165066), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-2 (ENSG00000229544), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

Homeobox protein Nkx-3.1 — Q99801 (reviewed: Q99801)

Alternative names: Homeobox protein NK-3 homolog A

All UniProt accessions (1): Q99801

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor, which binds preferentially the consensus sequence 5’-TAAGT[AG]-3’ and can behave as a transcriptional repressor. Plays an important role in normal prostate development, regulating proliferation of glandular epithelium and in the formation of ducts in prostate. Acts as a tumor suppressor controlling prostate carcinogenesis, as shown by the ability to inhibit proliferation and invasion activities of PC-3 prostate cancer cells.

Subunit / interactions. Interacts with serum response factor (SRF). Interacts with SPDEF. Interacts with WDR77. Interacts with TOPORS which polyubiquitinates NKX3-1 and induces its proteasomal degradation. Interacts with FEM1B.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in the prostate and, at a lower level, in the testis.

Post-translational modifications. Ubiquitinated by TOPORS; monoubiquitinated at several residues and also polyubiquitinated on single residues.

Induction. By androgens and, in the LNCaP cell line, by estrogens. Androgenic control may be lost in prostate cancer cells during tumor progression from an androgen-dependent to an androgen-independent phase.

Similarity. Belongs to the NK-3 homeobox family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q99801-1	1	yes
Q99801-2	2, V2
Q99801-3	3, V4
Q99801-4	4, V3
Q99801-5	5, V1

RefSeq proteins (2): NP_001243268, NP_006158* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050394	Homeobox_NK-like	Family

Pfam: PF00046

UniProt features (20 total): sequence conflict 6, splice variant 4, helix 3, compositionally biased region 2, chain 1, DNA-binding region 1, strand 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L9R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99801-F1	66.73	0.26

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 283 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_GLAND_MORPHOGENESIS, GOBP_METANEPHROS_DEVELOPMENT, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_SALIVARY_GLAND_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), metanephros development (GO:0001656), somitogenesis (GO:0001756), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), DNA damage response (GO:0006974), salivary gland development (GO:0007431), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), male gonad development (GO:0008584), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), androgen receptor signaling pathway (GO:0030521), regulation of protein localization (GO:0032880), response to testosterone (GO:0033574), dorsal aorta development (GO:0035907), negative regulation of insulin-like growth factor receptor signaling pathway (GO:0043569), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of transcription by RNA polymerase II (GO:0045944), branching morphogenesis of an epithelial tube (GO:0048754), negative regulation of epithelial cell proliferation (GO:0050680), positive regulation of cell division (GO:0051781), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), pharyngeal system development (GO:0060037), branching involved in prostate gland morphogenesis (GO:0060442), epithelial cell proliferation involved in salivary gland morphogenesis (GO:0060664), epithelial cell proliferation involved in prostate gland development (GO:0060767), negative regulation of epithelial cell proliferation involved in prostate gland development (GO:0060770), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to steroid hormone stimulus (GO:0071383), cellular response to hypoxia (GO:0071456), cellular response to xenobiotic stimulus (GO:0071466), positive regulation of androgen secretion (GO:2000836), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), urogenital system development (GO:0001655), apoptotic process (GO:0006915)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), nuclear estrogen receptor binding (GO:0030331), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), MADS box domain binding (GO:0097162), DNA-binding transcription factor binding (GO:0140297), transcription regulator inhibitor activity (GO:0140416), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), site of DNA damage (GO:0090734)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	4
regulation of DNA-templated transcription	4
cellular anatomical structure	4
DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
gene expression	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription regulator activity	2
chromosome	2
negative regulation of DNA-templated transcription	1
kidney development	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
regulation of RNA biosynthetic process	1
cellular response to stress	1
exocrine system development	1
gland development	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gonad development	1
development of primary male sexual characteristics	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
cellular developmental process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
intracellular protein localization	1
regulation of localization	1
response to lipid	1
response to ketone	1
aorta development	1
negative regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
insulin-like growth factor receptor signaling pathway	1

Protein interactions and networks

STRING

1320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NKX3-1	AR	P10275	917
NKX3-1	PTEN	P60484	784
NKX3-1	SPDEF	O95238	779
NKX3-1	KLK3	P07288	772
NKX3-1	TMPRSS2	O15393	721
NKX3-1	MSMB	P08118	703
NKX3-1	KLK2	P20151	695
NKX3-1	FOXA1	P55317	671
NKX3-1	FKBP5	Q13451	622
NKX3-1	SLC45A3	Q96JT2	620
NKX3-1	KLKB1	P03952	605
NKX3-1	KRT8	P05787	583
NKX3-1	AMACR	Q9UHK6	581
NKX3-1	KRT5	P13647	571
NKX3-1	SPOP	O43791	571

IntAct

25 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
NKX3-1	TOP1	psi-mi:“MI:0915”(physical association)	0.630
TOP1	NKX3-1	psi-mi:“MI:0915”(physical association)	0.630
NKX3-1	TOP1	psi-mi:“MI:0407”(direct interaction)	0.630
SLC67A1	NKX3-1	psi-mi:“MI:0915”(physical association)	0.560
ZNF417	NKX3-1	psi-mi:“MI:0915”(physical association)	0.560
NKX3-1	RHOXF2	psi-mi:“MI:0915”(physical association)	0.560
CD200R1L	NKX3-1	psi-mi:“MI:0915”(physical association)	0.560
RNF4	NKX3-1	psi-mi:“MI:0915”(physical association)	0.560
	NKX3-1	psi-mi:“MI:0407”(direct interaction)	0.440
NKX3-1	HIRA	psi-mi:“MI:0915”(physical association)	0.400
NKX3-1	ZNF417	psi-mi:“MI:0915”(physical association)	0.000
SLC67A1	NKX3-1	psi-mi:“MI:0915”(physical association)	0.000
RHOXF2	NKX3-1	psi-mi:“MI:0915”(physical association)	0.000
NKX3-1	CD200R1L	psi-mi:“MI:0915”(physical association)	0.000
NKX3-1	RNF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (65): NKX3-1 (Affinity Capture-MS), NKX3-1 (Two-hybrid), NKX3-1 (Two-hybrid), NKX3-1 (Two-hybrid), ZNF417 (Two-hybrid), CD200R1L (Two-hybrid), NKX3-1 (Affinity Capture-Western), NKX3-1 (Two-hybrid), NKX3-1 (Affinity Capture-Western), NKX3-1 (Affinity Capture-MS), HIRA (Affinity Capture-MS), NKX3-1 (Reconstituted Complex), NKX3-1 (Affinity Capture-Western), ATM (Affinity Capture-Western), NKX3-1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PPF3, A1A546, A1YGA4, A2T779, A2T7T2, A5YC49, A6NFQ7, A6NMT0, A6NNA5, F1Q4R9, O08686, O42173, O42358, P17278, P17482, P20615, P31272, P43688, P52950, P70368, P70436, P97436, P97458, Q01703, Q28ET4, Q2M1V0, Q3LU38, Q3LU39, Q3LU40, Q5NSW5, Q5TIS6, Q5TM83, Q61658, Q62798, Q80Z64, Q8BYH0, Q8JJ26, Q8MJI9, Q91926, Q92988

Diamond homologs: A0JPN1, A1YG85, A5PKG8, A6NJ46, A6NMT0, A7MB54, A9L937, B0VXK3, D2KQB0, E7FDX5, M0R6D8, O08686, O13023, O35762, O42365, O43364, O43711, O55144, O88181, O93366, O93367, O93590, P0C1T1, P10035, P14652, P14837, P20009, P28468, P31245, P31246, P31261, P31314, P42583, P42584, P43120, P43345, P43688, P50219, P52945, P52950

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
CSNK2A2	up-regulates	NKX3-1	phosphorylation
AR	“up-regulates quantity by expression”	NKX3-1	“transcriptional regulation”
NKX3-1	“down-regulates quantity by repression”	AR	“transcriptional regulation”
NKX3-1	“up-regulates quantity by stabilization”	TP53
NKX3-1	“down-regulates activity”	HDAC1	binding
NKX3-1	“down-regulates activity”	AKT
ERG	“down-regulates quantity by repression”	NKX3-1	“transcriptional regulation”
NKX3-1	“up-regulates quantity by expression”	ACTG2	“transcriptional regulation”
ATM	“down-regulates quantity by destabilization”	NKX3-1	phosphorylation
PTEN	“up-regulates quantity by stabilization”	NKX3-1	dephosphorylation
LIMK2	“down-regulates activity”	NKX3-1	phosphorylation
DYRK1B	“down-regulates quantity by destabilization”	NKX3-1	phosphorylation
ATM	“down-regulates quantity”	NKX3-1	phosphorylation
NKX3-1	“form complex”	NKX3-1/SRF	binding
PRKCA	up-regulates	NKX3-1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

162 predictions. Top by Δscore:

Variant	Effect	Δscore
8:23681636:CTTT:C	acceptor_gain	1.0000
8:23681640:C:CC	acceptor_gain	1.0000
8:23682598:GCTTA:G	donor_loss	1.0000
8:23682599:CTTAC:C	donor_loss	1.0000
8:23682600:TTACC:T	donor_loss	1.0000
8:23682601:TACCT:T	donor_loss	1.0000
8:23682602:A:AC	donor_gain	1.0000
8:23682603:C:CA	donor_loss	1.0000
8:23682603:C:CC	donor_gain	1.0000
8:23682603:CCTGG:C	donor_gain	1.0000
8:23681637:TTT:T	acceptor_gain	0.9900
8:23681637:TTTC:T	acceptor_loss	0.9900
8:23681640:C:G	acceptor_loss	0.9900
8:23681652:G:GC	acceptor_gain	0.9900
8:23682602:AC:A	donor_gain	0.9900
8:23682603:CC:C	donor_gain	0.9900
8:23681638:TT:T	acceptor_gain	0.9800
8:23681652:G:C	acceptor_gain	0.9800
8:23682603:CCTG:C	donor_gain	0.9800
8:23681666:A:C	acceptor_gain	0.9700
8:23682603:CCT:C	donor_gain	0.9700
8:23681666:A:AC	acceptor_gain	0.9100
8:23682015:T:TA	donor_gain	0.8400
8:23681545:G:T	acceptor_gain	0.8000
8:23681633:TGC:T	acceptor_gain	0.7900
8:23682126:TCATC:T	acceptor_gain	0.7300
8:23682664:G:C	donor_gain	0.7200
8:23681543:C:CA	acceptor_gain	0.6900
8:23682003:G:T	donor_gain	0.6700
8:23682130:C:CT	acceptor_gain	0.6500

AlphaMissense

1496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:23681406:T:C	N174D	1.000
8:23681407:C:A	Q173H	1.000
8:23681407:C:G	Q173H	1.000
8:23681410:G:C	F172L	1.000
8:23681410:G:T	F172L	1.000
8:23681411:A:C	F172C	1.000
8:23681411:A:G	F172S	1.000
8:23681412:A:C	F172V	1.000
8:23681412:A:G	F172L	1.000
8:23681412:A:T	F172I	1.000
8:23681413:C:A	W171C	1.000
8:23681413:C:G	W171C	1.000
8:23681415:A:G	W171R	1.000
8:23681415:A:T	W171R	1.000
8:23681438:A:G	L163P	1.000
8:23681483:T:C	Y148C	1.000
8:23681484:A:G	Y148H	1.000
8:23681497:G:C	F143L	1.000
8:23681497:G:T	F143L	1.000
8:23681498:A:C	F143C	1.000
8:23681498:A:G	F143S	1.000
8:23681499:A:G	F143L	1.000
8:23681510:A:G	L139S	1.000
8:23681533:G:C	F131L	1.000
8:23681533:G:T	F131L	1.000
8:23681534:A:C	F131C	1.000
8:23681534:A:G	F131S	1.000
8:23681535:A:G	F131L	1.000
8:23681386:C:A	K180N	0.999
8:23681386:C:G	K180N	0.999

dbSNP variants (sampled 300 via entrez): RS1001460327 (8:23680172 T>A,C), RS1001814841 (8:23679795 A>C), RS1001941445 (8:23684696 C>A), RS1002442915 (8:23680164 G>A), RS1003936267 (8:23678682 TCACA>T), RS1004321575 (8:23684730 C>G,T), RS1005060813 (8:23682252 G>A), RS1005079481 (8:23679020 C>T), RS1005373058 (8:23683571 C>A,T), RS1005694039 (8:23680107 T>A), RS1005763040 (8:23681737 T>A,C), RS1007600850 (8:23680662 C>A), RS1008066229 (8:23681064 A>C), RS1008375141 (8:23679755 T>C), RS1008708491 (8:23681127 C>A,T)

Disease associations

OMIM: gene MIM:602041 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000488_10	Prostate cancer	3.000000e-30
GCST000750_7	Prostate cancer	4.000000e-11
GCST003148_9	Prostate cancer	1.000000e-13
GCST004064_20	Waist-hip ratio	5.000000e-09
GCST004093_31	Prostate-specific antigen levels	4.000000e-34
GCST005957_7	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-06
GCST005958_10	Waist-to-hip ratio adjusted for BMI (age >50)	3.000000e-08
GCST005962_21	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	5.000000e-11
GCST005992_13	Mean corpuscular hemoglobin concentration	8.000000e-10
GCST005993_41	Mean corpuscular hemoglobin	1.000000e-10
GCST008362_176	Birth weight	1.000000e-11
GCST008860_26	Prostate cancer	3.000000e-24
GCST011829_6	Prostate cancer	8.000000e-16
GCST90002424_3	Prostate cancer	3.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004527	mean corpuscular hemoglobin
EFO:0004344	birth weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Metribolone	increases expression, affects binding, increases reaction, decreases expression, affects reaction (+1 more)	9
bicalutamide	decreases reaction, increases expression, decreases expression, affects cotreatment	4
Asbestos, Crocidolite	affects expression, decreases expression, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Resveratrol	decreases expression	3
Estradiol	increases expression, affects reaction, affects cotreatment, decreases reaction	3
Dihydrotestosterone	increases expression, decreases expression, decreases reaction	3
Valproic Acid	increases expression	3
enzalutamide	decreases expression, increases reaction	2
Acetaminophen	increases expression	2
Androgens	increases expression, decreases reaction	2
Curcumin	decreases expression	2
Quercetin	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	affects expression, increases expression	2
Cadmium Chloride	decreases reaction, increases expression	2
Genistein	decreases expression	2
aristolochic acid I	increases expression	1
NVP-BHG712	decreases expression, increases reaction	1
daidzein	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
methylselenic acid	affects expression	1
tetramethrin	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
phentin acetate	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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