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NKX2-8

gene
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Also known as NKX2.8Nkx2-9

Summary

NKX2-8 (NK2 homeobox 8, HGNC:16364) is a protein-coding gene on chromosome 14q13.3, encoding Homeobox protein Nkx-2.8 (O15522).

The protein encoded by this gene is a homeobox-containing developmental regulator associated with liver development. The encoded protein binds to the alpha-fetoprotein (AFP) gene promoter and increases the expression of AFP. This gene is overexpressed in some lung cancers and is linked to poor patient survival, possibly due to its resistance to cisplatin. This gene is aberrantly methylated in pancreatic cancer, deleted in squamous cell lung carcinomas, and acts as a tumor suppressor in esophageal cancer. Mutations in this gene may also be a cause of neural tube defects.

Source: NCBI Gene 26257 — RefSeq curated summary.

At a glance

  • GWAS associations: 3
  • Clinical variants (ClinVar): 52 total — 1 pathogenic
  • MANE Select transcript: NM_014360

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:16364
Approved symbolNKX2-8
NameNK2 homeobox 8
Location14q13.3
Locus typegene with protein product
StatusApproved
AliasesNKX2.8, Nkx2-9
Ensembl geneENSG00000136327
Ensembl biotypeprotein_coding
OMIM603245
Entrez26257

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000258829

RefSeq mRNA: 1 — MANE Select: NM_014360 NM_014360

CCDS: CCDS9660

Canonical transcript exons

ENST00000258829 — 2 exons

ExonStartEnd
ENSE000009302003658000436581464
ENSE000020437783658223336582614

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 69.54.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7869 / max 143.9700, expressed in 292 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
1429560.5039251
1429530.1999128
1429550.052417
1429540.030610

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
C1 segment of cervical spinal cordUBERON:000646969.54gold quality
spinal cordUBERON:000224067.06gold quality
right testisUBERON:000453465.30gold quality
tendon of biceps brachiiUBERON:000818864.68gold quality
lower esophagus mucosaUBERON:003583464.41gold quality
left testisUBERON:000453364.31gold quality
buccal mucosa cellCL:000233662.65gold quality
testisUBERON:000047362.16gold quality
esophagus mucosaUBERON:000246960.30gold quality
medial globus pallidusUBERON:000247758.30gold quality
oviduct epitheliumUBERON:000480456.60gold quality
esophagus squamous epitheliumUBERON:000692056.26gold quality
skin of hipUBERON:000155454.56silver quality
globus pallidusUBERON:000187554.43gold quality
upper leg skinUBERON:000426253.52silver quality
parotid glandUBERON:000183153.41gold quality
Brodmann (1909) area 46UBERON:000648352.63gold quality
left lobe of thyroid glandUBERON:000112052.60gold quality
thyroid glandUBERON:000204651.85gold quality
adenohypophysisUBERON:000219651.61gold quality
hypothalamusUBERON:000189851.46gold quality
deciduaUBERON:000245051.02gold quality
right lobe of thyroid glandUBERON:000111950.36gold quality
adult organismUBERON:000702350.05gold quality
bronchial epithelial cellCL:000232849.43gold quality
blood vessel layerUBERON:000479749.29gold quality
dorsal motor nucleus of vagus nerveUBERON:000287049.24gold quality
substantia nigraUBERON:000203849.02gold quality
bronchusUBERON:000218548.99gold quality
choroid plexus epitheliumUBERON:000391148.89gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no1.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

TargetRegulation
AFPUnknown
AKIP1

JASPAR motifs

MotifNameFamily
MA0673.1NKX2-8NK
MA0673.2NKX2-8NK

JASPAR matrix evidence (PMIDs): PMID:11042197

Upstream regulators (CollecTRI, top): GLI1, NFKB

miRNA regulators (miRDB)

20 targeting NKX2-8, 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-LET-7F-1-3P100.0074.023928
HSA-MIR-4283100.0066.422097
HSA-LET-7A-3P100.0074.033932
HSA-LET-7B-3P100.0074.083913
HSA-MIR-98-3P100.0074.083907
HSA-MIR-185-3P99.9567.011743
HSA-MIR-449299.8768.253611
HSA-MIR-1249-5P99.6166.552049
HSA-MIR-6797-5P99.6166.552084
HSA-MIR-141-5P99.5767.86897
HSA-MIR-516A-3P99.4667.961378
HSA-MIR-516B-3P99.4667.961378
HSA-MIR-7162-5P99.4668.081368
HSA-MIR-361-3P99.1966.451381
HSA-MIR-6829-5P98.8665.121480
HSA-MIR-6511B-5P97.9865.64823
HSA-MIR-6811-5P97.9864.96848
HSA-MIR-4423-3P97.9869.66912
HSA-MIR-514A-5P96.9465.49801
HSA-MIR-6789-3P83.9159.7758

Literature-anchored findings (GeneRIF, showing 8)

  • A murine Nkx2.8 was isolated from the Hepal-6 cell line and showed oligonucleotide binding competitive with fetoprotein transcription factor. (PMID:12167706)
  • Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of lung cancer patients with poor survival and were shown to exhibit resistance to cisplatin (PMID:19279207)
  • Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells. (PMID:21148747)
  • overexpression of Nkx2.8 resulted in downregulation of p-FOXO3a and inhibition of MEK/ERK pathway activity. silencing Nkx2.8 led to upregulation of p-FOXO3a and increase of MEK/ERK pathway activity. (PMID:22223847)
  • Results show that Nkx2-8 functions as a tumor suppressor in esophageal squamous cell carcinoma (ESCC), the downregulation of which contributes to NF-kappaB P65 activation and ESCC angiogenesis. (PMID:23604637)
  • Low NKX2-8 expression is associated with Bladder Urothelial Carcinoma. (PMID:29311157)
  • Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. (PMID:31047858)
  • Nkx2.8 promotes chemosensitivity in bladder urothelial carcinoma via transcriptional repression of MDR1. (PMID:35610207)

Cross-species orthologs

9 orthologs

OrganismSymbolGene ID
mus_musculusNkx2-9ENSMUSG00000058669
rattus_norvegicusNkx2-8ENSRNOG00000022970
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), NKX2-1 (ENSG00000136352), NKX6-2 (ENSG00000148826), NKX6-1 (ENSG00000163623), NKX6-3 (ENSG00000165066), NKX3-1 (ENSG00000167034), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-2 (ENSG00000229544), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

Homeobox protein Nkx-2.8 — O15522 (reviewed: O15522)

Alternative names: Homeobox protein NK-2 homolog H

All UniProt accessions (1): O15522

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Similarity. Belongs to the NK-2 homeobox family.

RefSeq proteins (1): NP_055175* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001356HDDomain
IPR009057Homeodomain-like_sfHomologous_superfamily
IPR017970Homeobox_CSConserved_site
IPR020479HD_metazoaDomain
IPR050394Homeobox_NK-likeFamily

Pfam: PF00046

UniProt features (8 total): compositionally biased region 3, chain 1, DNA-binding region 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-O15522-F168.380.26

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, PAX2_01, TCF4_Q5, ZIC1_01, LYF1_01, NKX22_01, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, GFI1_01, RYTTCCTG_ETS2_B, chr14q13, YAGI_AML_WITH_11Q23_REARRANGED, WGTTNNNNNAAA_UNKNOWN

GO Biological Process (12): liver development (GO:0001889), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), axonogenesis (GO:0007409), cell differentiation (GO:0030154), lung development (GO:0030324), positive regulation of transcription by RNA polymerase II (GO:0045944), epithelial cell proliferation (GO:0050673), negative regulation of epithelial cell proliferation (GO:0050680), regulation of DNA-templated transcription (GO:0006355), respiratory tube development (GO:0030323)

GO Molecular Function (8): 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 activator activity, RNA polymerase II-specific (GO:0001228), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), 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 binding3
regulation of DNA-templated transcription2
transcription by RNA polymerase II2
DNA-templated transcription2
animal organ development2
regulation of transcription by RNA polymerase II2
DNA binding2
gland development1
hepaticobiliary system development1
gene expression1
RNA biosynthetic process1
cell morphogenesis involved in neuron differentiation1
neuron projection morphogenesis1
axon development1
cellular developmental process1
respiratory tube development1
respiratory system development1
positive regulation of DNA-templated transcription1
cell population proliferation1
negative regulation of cell population proliferation1
epithelial cell proliferation1
regulation of epithelial cell proliferation1
regulation of gene expression1
regulation of RNA biosynthetic process1
tube development1
cis-regulatory region sequence-specific DNA binding1
chromatin1
DNA-binding transcription factor activity1
DNA-binding transcription factor activity, RNA polymerase II-specific1
DNA-binding transcription activator activity1
positive regulation of transcription by RNA polymerase II1
transcription cis-regulatory region binding1
transcription regulator activity1
double-stranded DNA binding1
sequence-specific DNA binding1
nucleic acid binding1
chromosome1
cellular anatomical structure1
intracellular membrane-bounded organelle1

Protein interactions and networks

STRING

648 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
NKX2-8PAX9P55771901
NKX2-8SMYD3Q9H7B4862
NKX2-8HELZP42694827
NKX2-8AFPP02771519
NKX2-8OTX1P32242425
NKX2-8FOXA1P55317424
NKX2-8OTX2P32243420
NKX2-8MBIPQ9NS73405
NKX2-8SLC25A21Q9BQT8384
NKX2-8PITX1P78337381
NKX2-8NFKB2Q00653372
NKX2-8MYO18AO95411370
NKX2-8ATP11BQ9Y2G3368
NKX2-8CHP2O43745362
NKX2-8NKX6-3A6NJ46359
NKX2-8DCUN1D1Q96GG9359

IntAct

19 interactions, top by confidence:

ABTypeScore
NKX2-8AKT1psi-mi:“MI:0915”(physical association)0.450
AKT1NKX2-8psi-mi:“MI:2364”(proximity)0.450
FBXW7NKX2-8psi-mi:“MI:2364”(proximity)0.270
SMAD4NKX2-8psi-mi:“MI:2364”(proximity)0.270
NKX2-8SMAD4psi-mi:“MI:2364”(proximity)0.270
NKX2-8SMARCA4psi-mi:“MI:2364”(proximity)0.270
SMARCA4NKX2-8psi-mi:“MI:2364”(proximity)0.270
NKX2-8EGFRpsi-mi:“MI:2364”(proximity)0.270
NKX2-8PTENpsi-mi:“MI:2364”(proximity)0.270
NKX2-8PTPN11psi-mi:“MI:2364”(proximity)0.270
NKX2-8TP53psi-mi:“MI:2364”(proximity)0.270

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, G5EE18, O02786, O15522, O17319, O35767, O43763, O57601, O70218, O70584, O93590, O95096, P13297, P22711, P22808, P22809, P23410, P23441, P28360, P28361, P28362, P35548, P35993, P40764, P41936, P42581, P42582, P42583, P42584, P42586, P42587, P43687, P43688, P43697, P43698

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic1
Likely pathogenic0
Uncertain significance49
Likely benign0
Benign2

Top pathogenic / likely-pathogenic (1)

Variant IDHGVSClassification
8972NC_000014.8:g.(36407609_36463186)_(37638963_37670256)delPathogenic

SpliceAI

227 predictions. Top by Δscore:

VariantEffectΔscore
14:36581465:C:CCacceptor_gain1.0000
14:36582231:A:ACdonor_gain1.0000
14:36582232:C:CCdonor_gain1.0000
14:36581460:CGAGG:Cacceptor_gain0.9900
14:36581461:GAGG:Gacceptor_gain0.9900
14:36581462:AGG:Aacceptor_gain0.9900
14:36581463:GG:Gacceptor_gain0.9900
14:36581464:GCTAG:Gacceptor_loss0.9900
14:36581465:CTA:Cacceptor_loss0.9900
14:36581473:A:Tacceptor_gain0.9900
14:36581475:C:CTacceptor_gain0.9900
14:36582229:TTA:Tdonor_loss0.9900
14:36582230:TA:Tdonor_loss0.9900
14:36582232:CA:Cdonor_gain0.9900
14:36582232:CAAG:Cdonor_gain0.9900
14:36582232:CAAGG:Cdonor_gain0.9900
14:36581472:C:CTacceptor_gain0.9800
14:36581716:A:Cdonor_gain0.9800
14:36582227:A:ACdonor_gain0.9800
14:36582228:C:CCdonor_gain0.9800
14:36582232:CAA:Cdonor_gain0.9800
14:36581476:A:Tacceptor_gain0.9700
14:36581583:T:Adonor_gain0.9600
14:36582228:CTTA:Cdonor_gain0.9600
14:36581599:T:Adonor_gain0.9400
14:36581754:A:ACdonor_gain0.8900
14:36582229:T:Cdonor_gain0.8900
14:36581464:GCT:Gacceptor_gain0.8600
14:36581465:C:CAacceptor_gain0.8600
14:36582230:TACAA:Tdonor_gain0.8600

AlphaMissense

1497 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
14:36581226:G:CF132L1.000
14:36581226:G:TF132L1.000
14:36581228:A:GF132L1.000
14:36581221:T:CN134S0.999
14:36581222:T:CN134D0.999
14:36581227:A:CF132C0.999
14:36581227:A:GF132S0.999
14:36581313:G:CF103L0.999
14:36581313:G:TF103L0.999
14:36581315:A:GF103L0.999
14:36581326:A:GL99S0.999
14:36581349:G:CF91L0.999
14:36581349:G:TF91L0.999
14:36581350:A:CF91C0.999
14:36581350:A:GF91S0.999
14:36581351:A:GF91L0.999
14:36581208:C:AK138N0.998
14:36581208:C:GK138N0.998
14:36581220:A:CN134K0.998
14:36581220:A:TN134K0.998
14:36581221:T:AN134I0.998
14:36581221:T:GN134T0.998
14:36581223:C:AQ133H0.998
14:36581223:C:GQ133H0.998
14:36581228:A:CF132V0.998
14:36581228:A:TF132I0.998
14:36581229:C:AW131C0.998
14:36581229:C:GW131C0.998
14:36581233:A:CI130S0.998
14:36581233:A:GI130T0.998

dbSNP variants (sampled 300 via entrez): RS1000083871 (14:36583776 G>A), RS1001327309 (14:36584527 G>A), RS1001566772 (14:36581737 C>A,T), RS1001640210 (14:36581403 C>T), RS1001954386 (14:36580407 C>T), RS1002566221 (14:36582851 G>GCTT), RS1003953141 (14:36583498 C>A,T), RS1004192617 (14:36580184 C>T), RS1004393875 (14:36580360 C>G,T), RS1004409610 (14:36583149 G>A), RS1004424949 (14:36580095 G>C), RS1005394345 (14:36581352 T>C), RS1007487266 (14:36581097 A>C), RS1008038054 (14:36579735 C>T), RS1008081635 (14:36582408 G>A,T)

Disease associations

OMIM: gene MIM:603245 | disease phenotypes: MIM:118700

GenCC curated gene-disease

Mondo (1): hereditary progressive chorea without dementia (MONDO:0021011)

Orphanet (1): Benign hereditary chorea (Orphanet:1429)

HPO phenotypes

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

GWAS associations

3 associations (top):

StudyTraitp-value
GCST005192_43Lobe attachment (rater-scored or self-reported)3.000000e-66
GCST005193_2Lobe attachment (rater scored)5.000000e-09
GCST008839_356Height2.000000e-15

EFO canonical traits (1, from GWAS)

EFO IDTrait name
EFO:0007667lobe attachment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

ChemicalActions (top 5)PubMed papers
sodium arsenitedecreases expression, increases expression2
Air Pollutantsincreases abundance, increases expression2
Valproic Acidaffects expression, increases methylation2
Aflatoxin B1decreases methylation, increases methylation2
Particulate Matterincreases abundance, increases expression2
ferrous chloridedecreases expression1
S-(1,2-dichlorovinyl)cysteineaffects response to substance, increases expression1
abrineincreases expression1
Decitabineincreases expression1
Benzo(a)pyrenedecreases methylation1
Lipopolysaccharidesincreases expression, affects response to substance1
Tetrachlorodibenzodioxinincreases expression1
Tobacco Smoke Pollutionincreases expression1
Triclosanincreases expression1

Clinical trials (associated diseases)

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

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
v1.1.2
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