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NKX6-3

gene
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Also known as FLJ25169

Summary

NKX6-3 (NK6 homeobox 3, HGNC:26328) is a protein-coding gene on chromosome 8p11.21, encoding Homeobox protein Nkx-6.3 (A6NJ46). Putative transcription factor, which may be involved in patterning of central nervous system and pancreas.

The NKX family of homeodomain proteins controls numerous developmental processes. Members of the NKX6 subfamily, including NKX6-3, are involved in development of the central nervous system (CNS), gastrointestinal tract, and pancreas (Alanentalo et al., 2006 [PubMed 16326147]).

Source: NCBI Gene 157848 — RefSeq curated summary.

At a glance

  • GWAS associations: 3
  • Clinical variants (ClinVar): 17 total
  • Transcription factor: yes — 10 downstream targets (CollecTRI)
  • MANE Select transcript: NM_001364841

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:26328
Approved symbolNKX6-3
NameNK6 homeobox 3
Location8p11.21
Locus typegene with protein product
StatusApproved
AliasesFLJ25169
Ensembl geneENSG00000165066
Ensembl biotypeprotein_coding
OMIM610772
Entrez157848

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000518699, ENST00000524115

RefSeq mRNA: 2 — MANE Select: NM_001364841 NM_001364841, NM_152568

CCDS: CCDS6118, CCDS94289

Canonical transcript exons

ENST00000518699 — 3 exons

ExonStartEnd
ENSE000017109854164806641648235
ENSE000020951894165011141650817
ENSE000021322484164517741646694

Expression profiles

Bgee: expression breadth broad, 63 present calls, max score 78.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2010 / max 309.8856, expressed in 13 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter IDTPM avgSamples expressed
928310.186413
928300.01461

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099178.59gold quality
pylorusUBERON:000116678.35gold quality
duodenumUBERON:000211477.10gold quality
right hemisphere of cerebellumUBERON:001489076.83gold quality
cerebellar hemisphereUBERON:000224576.62gold quality
cerebellar cortexUBERON:000212976.50gold quality
cerebellumUBERON:000203775.80gold quality
buccal mucosa cellCL:000233674.65silver quality
parotid glandUBERON:000183174.12gold quality
superficial temporal arteryUBERON:000161473.04gold quality
vena cavaUBERON:000408772.48gold quality
spermCL:000001970.91gold quality
vastus lateralisUBERON:000137970.82gold quality
quadriceps femorisUBERON:000137770.75gold quality
cerebellar vermisUBERON:000472070.22silver quality
nasal cavity epitheliumUBERON:000538470.04gold quality
biceps brachiiUBERON:000150769.92gold quality
saphenous veinUBERON:000731868.41silver quality
skeletal muscle tissue of rectus abdominisUBERON:000451168.24gold quality
skeletal muscle tissue of biceps brachiiUBERON:000450268.06gold quality
myocardiumUBERON:000234967.35gold quality
pharyngeal mucosaUBERON:000035567.11gold quality
pericardiumUBERON:000240766.47gold quality
islet of LangerhansUBERON:000000666.03gold quality
ventral tegmental areaUBERON:000269166.01gold quality
subthalamic nucleusUBERON:000190665.70gold quality
tracheaUBERON:000312665.63gold quality
epithelium of nasopharynxUBERON:000195165.52gold quality
substantia nigra pars compactaUBERON:000196565.51gold quality
deltoidUBERON:000147665.47gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-MTAB-5061yes9.61
E-ANND-3no0.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

TargetRegulation
BAK1Activation
BBC3Activation
BCL2Repression
BCL3Repression
BNIP3Activation
GAST
GKN1Activation
MCL1Repression
MDM2Repression
PDCD4Activation

JASPAR motifs

MotifNameFamily
MA1530.1NKX6-3NK
MA1530.2NKX6-3NK

JASPAR matrix evidence (PMIDs): PMID:18585359

miRNA regulators (miRDB)

31 targeting NKX6-3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-5193100.0067.261744
HSA-MIR-118499.9968.191458
HSA-MIR-6778-3P99.9667.292693
HSA-MIR-3065-3P99.8770.251407
HSA-MIR-1211999.8768.351653
HSA-MIR-383-3P99.8565.841359
HSA-MIR-4659A-3P99.8072.624248
HSA-MIR-4659B-3P99.8072.624248
HSA-MIR-6887-3P99.6667.831778
HSA-MIR-452-5P99.6569.631762
HSA-MIR-4676-3P99.6569.311733
HSA-MIR-892C-3P99.6569.381745
HSA-MIR-3158-5P99.6567.511763
HSA-MIR-4667-3P99.2665.451608
HSA-MIR-6749-3P99.0065.731443
HSA-MIR-4725-5P98.6765.42628
HSA-MIR-504-5P98.6765.40631
HSA-MIR-797798.6566.182590
HSA-MIR-1227-5P98.6565.321549
HSA-MIR-6792-3P98.4166.861359
HSA-MIR-4691-5P98.4166.771343
HSA-MIR-6826-3P98.1966.321153
HSA-MIR-660-3P98.1466.041434
HSA-MIR-446997.9365.811319
HSA-MIR-425797.8668.051190
HSA-MIR-1914-5P97.8366.21807
HSA-MIR-6747-3P97.7364.841596
HSA-MIR-4676-5P97.5465.29715
HSA-MIR-57597.5465.18718
HSA-MIR-365A-5P94.9163.72471

Literature-anchored findings (GeneRIF, showing 7)

  • Data suggest that NK6 homeobox 3 (NKX6.3) may control the fate of gastric mucosal cells and function as a gastric tumor suppressor. (PMID:26314965)
  • Suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6.3 inactivation may result in intestinal metaplasia in gastric epithelial cells. (PMID:26743476)
  • The expression level of NKX6.3 is involved in regulation of gastric cancer progression and expression of Wnt/beta-catenin and Rho-GTPase pathway-related genes in clinical samples. (PMID:27333045)
  • these results suggest that NKX6.3 inhibits ROS production by inducing the expression of Hace1 via down-regulating NF-kB and DNMT1 activity in gastric epithelial cells. (PMID:28584243)
  • These results indicate that NKX6.3 depletion in gastric epithelial cells activates AICDA/APOBEC family, leading to accumulation of genetic mutations and eventually driving the development of gastric cancers. (PMID:30514953)
  • NKX6.3 inhibits gastric mucosal atrophy by regulating amyloid beta accumulation and inflammatory reaction in gastric epithelial cells. (PMID:30686901)
  • These results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control. (PMID:30710084)

Cross-species orthologs

10 orthologs

OrganismSymbolGene ID
danio_rerionkx6.3ENSDARG00000060529
mus_musculusNkx6-3ENSMUSG00000063672
rattus_norvegicusNkx6-3ENSRNOG00000018147
drosophila_melanogasterNK7.1FBGN0024321
drosophila_melanogasterHGTXFBGN0040318
drosophila_melanogasterscroFBGN0287186
caenorhabditis_elegansceh-9WBGENE00000434
caenorhabditis_elegansWBGENE00000447
caenorhabditis_elegansWBGENE00000450
caenorhabditis_elegansWBGENE00000584

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), NKX3-1 (ENSG00000167034), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-2 (ENSG00000229544), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

Homeobox protein Nkx-6.3 — A6NJ46 (reviewed: A6NJ46)

All UniProt accessions (1): A6NJ46

UniProt curated annotations — full annotation on UniProt →

Function. Putative transcription factor, which may be involved in patterning of central nervous system and pancreas.

Subcellular location. Nucleus.

Isoforms (2)

UniProt IDNamesCanonical?
A6NJ46-11yes
A6NJ46-22

RefSeq proteins (2): NP_001351770, NP_689781 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000047HTH_motifConserved_site
IPR001356HDDomain
IPR009057Homeodomain-like_sfHomologous_superfamily
IPR017970Homeobox_CSConserved_site
IPR020479HD_metazoaDomain
IPR050394Homeobox_NK-likeFamily

Pfam: PF00046

UniProt features (4 total): chain 1, DNA-binding region 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-A6NJ46-F164.530.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_COLUMNAR_CUBOIDAL_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_CELL_FATE_DETERMINATION, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_CELL_FATE_COMMITMENT, GOBP_GLANDULAR_EPITHELIAL_CELL_DIFFERENTIATION, ER_Q6_02, CCAWNWWNNNGGC_UNKNOWN, COUP_DR1_Q6, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MARTENS_TRETINOIN_RESPONSE_UP, GOBP_NEGATIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate determination (GO:0001709), glandular epithelial cell differentiation (GO:0002067), regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), stomach neuroendocrine cell differentiation (GO:0061102), negative regulation of stomach neuroendocrine cell differentiation (GO:0061106), regulation of DNA-templated transcription (GO:0006355), enteroendocrine cell differentiation (GO:0035883), neuroendocrine cell differentiation (GO:0061101)

GO Molecular Function (7): 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
RNA polymerase II transcription regulatory region sequence-specific DNA binding4
regulation of transcription by RNA polymerase II3
transcription by RNA polymerase II3
cellular developmental process2
DNA-binding transcription factor activity, RNA polymerase II-specific2
negative regulation of DNA-templated transcription1
cell fate commitment1
columnar/cuboidal epithelial cell differentiation1
regulation of DNA-templated transcription1
positive regulation of DNA-templated transcription1
enteroendocrine cell differentiation1
neuroendocrine cell differentiation1
stomach development1
inhibition of neuroepithelial cell differentiation1
negative regulation of neuron differentiation1
stomach neuroendocrine cell differentiation1
regulation of stomach neuroendocrine cell differentiation1
negative regulation of enteroendocrine cell differentiation1
DNA-templated transcription1
regulation of gene expression1
regulation of RNA biosynthetic process1
epithelial cell differentiation1
neuron differentiation1
neuroepithelial cell differentiation1
cis-regulatory region sequence-specific DNA binding1
chromatin1
DNA-binding transcription factor activity1
negative regulation of transcription by RNA polymerase II1
DNA-binding transcription repressor activity1
DNA-binding transcription activator activity1
positive regulation of transcription by RNA polymerase II1
DNA binding1
double-stranded DNA binding1
sequence-specific DNA binding1
nucleic acid binding1
chromosome1
cellular anatomical structure1
intracellular membrane-bounded organelle1

Protein interactions and networks

STRING

592 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
NKX6-3NKX2-3Q8TAU0532
NKX6-3HHEXQ03014486
NKX6-3NKX1-1Q15270477
NKX6-3RNF6Q9Y252476
NKX6-3HLXQ14774475
NKX6-3TLX2O43763471
NKX6-3NKX3-1Q99801449
NKX6-3GLIS2Q9BZE0447
NKX6-3CEP72Q9P209447
NKX6-3LARP6Q9BRS8444
NKX6-3SLC35D3Q5M8T2435
NKX6-3VENTXO95231432
NKX6-3SLC30A8Q8IWU4418
NKX6-3IGF2BP2Q9Y6M1415
NKX6-3LYPLAL1Q5VWZ2405
NKX6-3NKX3-2P78367405

IntAct

0 interactions, top by confidence:

BioGRID (1): NKX6-3 (Synthetic Lethality)

ESM2 similar proteins: A1YEY5, A1YFA5, A1YFI3, A1YG57, A2T733, A2T764, A2T7P4, A6NJ46, O42115, O43248, O43711, O55144, O95096, P02830, P09023, P09024, P09629, P09633, P17509, P17919, P18864, P23410, P28362, P29454, P31259, P31311, P31313, P31315, P42586, P43120, P43345, P43697, P48031, P52951, P53544, P53545, P53546, P56915, P97334, Q02591

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

1 interactions.

AEffectBMechanism
NKX6-3“up-regulates quantity by expression”GKN1“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance15
Likely benign0
Benign1

Top pathogenic / likely-pathogenic (0)

SpliceAI

341 predictions. Top by Δscore:

VariantEffectΔscore
8:41648061:CTTA:Cdonor_loss1.0000
8:41648062:TTA:Tdonor_loss1.0000
8:41648063:TA:Tdonor_loss1.0000
8:41648064:A:ACdonor_gain1.0000
8:41648064:A:Cdonor_loss1.0000
8:41648065:C:CCdonor_gain1.0000
8:41648231:TGGGG:Tacceptor_gain1.0000
8:41648232:GGGG:Gacceptor_gain1.0000
8:41648233:GGG:Gacceptor_gain1.0000
8:41648234:GG:Gacceptor_gain1.0000
8:41648236:C:CCacceptor_gain1.0000
8:41648240:C:CTacceptor_gain1.0000
8:41648241:A:Tacceptor_gain1.0000
8:41646690:CACAC:Cacceptor_gain0.9900
8:41646692:CAC:Cacceptor_gain0.9900
8:41646693:ACCT:Aacceptor_loss0.9900
8:41646695:C:CAacceptor_loss0.9900
8:41646696:T:Gacceptor_loss0.9900
8:41648064:AC:Adonor_gain0.9900
8:41648065:CC:Cdonor_gain0.9900
8:41648065:CCT:Cdonor_gain0.9900
8:41648067:TTG:Tdonor_gain0.9900
8:41650109:A:ACdonor_gain0.9900
8:41650110:C:CCdonor_gain0.9900
8:41646700:A:ACacceptor_gain0.9800
8:41648068:TG:Tdonor_gain0.9800
8:41646695:C:CCacceptor_gain0.9700
8:41646691:ACAC:Aacceptor_gain0.9500
8:41646692:CACC:Cacceptor_gain0.9500
8:41646693:AC:Aacceptor_gain0.9200

AlphaMissense

1715 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
8:41646668:C:AK193N1.000
8:41646668:C:GK193N1.000
8:41646670:T:CK193E1.000
8:41646674:C:AR191S1.000
8:41646674:C:GR191S1.000
8:41646675:C:AR191M1.000
8:41646675:C:GR191T1.000
8:41646676:T:AR191W1.000
8:41646676:T:CR191G1.000
8:41646678:C:GR190P1.000
8:41646679:G:AR190C1.000
8:41646679:G:CR190G1.000
8:41646679:G:TR190S1.000
8:41646680:G:CN189K1.000
8:41646680:G:TN189K1.000
8:41646681:T:AN189I1.000
8:41646681:T:CN189S1.000
8:41646681:T:GN189T1.000
8:41646682:T:CN189D1.000
8:41646682:T:GN189H1.000
8:41646683:C:AQ188H1.000
8:41646683:C:GQ188H1.000
8:41646684:T:GQ188P1.000
8:41646686:G:CF187L1.000
8:41646686:G:TF187L1.000
8:41646687:A:CF187C1.000
8:41646687:A:GF187S1.000
8:41646688:A:CF187V1.000
8:41646688:A:GF187L1.000
8:41646688:A:TF187I1.000

dbSNP variants (sampled 300 via entrez): RS1000170234 (8:41645285 C>A,G,T), RS1000201546 (8:41645570 T>C), RS1000537329 (8:41647008 G>C), RS1000732205 (8:41650361 G>A,C,T), RS1001373457 (8:41650731 G>A), RS1001554669 (8:41650783 C>A), RS1001718467 (8:41650509 C>G), RS1001837016 (8:41651177 A>G), RS1002298678 (8:41646256 C>T), RS1002434519 (8:41646007 C>A), RS1003656821 (8:41649358 C>T), RS1003876258 (8:41646039 C>A,G), RS1004115918 (8:41649580 C>T), RS1005014220 (8:41651423 T>C), RS1005067911 (8:41651750 C>G)

Disease associations

OMIM: gene MIM:610772 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

StudyTraitp-value
GCST006804_51Red cell distribution width5.000000e-13
GCST008362_115Birth weight2.000000e-10
GCST010118_163Type 2 diabetes5.000000e-28

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0009188Red cell distribution width
EFO:0004344birth weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

ChemicalActions (top 5)PubMed papers
S-(1,2-dichlorovinyl)cysteineaffects response to substance, increases expression1
Acetaminophendecreases expression1
Benzo(a)pyreneaffects methylation1
Lipopolysaccharidesdecreases expression, affects response to substance, increases expression1
Tobacco Smoke Pollutiondecreases methylation1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

CellosaurusNameCategorySex
CVCL_A4R5SEES3-1V human NKX6-3, clone1Embryonic stem cellMale
CVCL_A4R6SEES3-1V human NKX6-3, clone2Embryonic stem cellMale
CVCL_A4R7SEES3-1V human NKX6-3, clone3Embryonic stem cellMale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.4
BioBTree
v2.0.2

Sources 74

This page pulls from 74 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomerefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot