ZBED3

Summary

ZBED3 (zinc finger BED-type containing 3, HGNC:20711) is a protein-coding gene on chromosome 5q13.3, encoding Zinc finger BED domain-containing protein 3 (Q96IU2). Acts as a positive regulator in the activation of the canonical Wnt/beta-catenin signaling pathway by stabilizing cytoplasmic beta-catenin.

This gene belongs to a class of genes that arose through hAT DNA transposition and that encode regulatory proteins. This gene is upregulated in lung cancer tissues, where the encoded protein causes an accumulation of beta-catenin and enhanced lung cancer cell invasion. In addition, the encoded protein can be secreted and be involved in resistance to insulin.

Source: NCBI Gene 84327 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 13 total
• MANE Select transcript: NM_032367

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20711
Approved symbol	ZBED3
Name	zinc finger BED-type containing 3
Location	5q13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC15435
Ensembl gene	ENSG00000132846
Ensembl biotype	protein_coding
OMIM	615250
Entrez	84327

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000255198, ENST00000505685, ENST00000511587, ENST00000896398, ENST00000896399, ENST00000896400, ENST00000896401, ENST00000896402, ENST00000896403, ENST00000952243

RefSeq mRNA: 2 — MANE Select: NM_032367 NM_001329564, NM_032367

CCDS: CCDS4036

Canonical transcript exons

ENST00000255198 — 3 exons

Exon	Start	End
ENSE00001082783	77078594	77078728
ENSE00001082784	77087111	77087285
ENSE00001169455	77072072	77077895

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 88.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.4133 / max 217.0966, expressed in 1477 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62178	3.2435	1182
62179	1.5352	757
62180	1.4561	756
62177	0.1785	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	88.11	silver quality
left ventricle myocardium	UBERON:0006566	83.09	gold quality
secondary oocyte	CL:0000655	82.67	gold quality
ileal mucosa	UBERON:0000331	82.43	gold quality
pigmented layer of retina	UBERON:0001782	82.22	gold quality
smooth muscle tissue	UBERON:0001135	81.55	gold quality
left lobe of thyroid gland	UBERON:0001120	81.46	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.33	gold quality
right lobe of thyroid gland	UBERON:0001119	81.26	gold quality
parotid gland	UBERON:0001831	81.08	gold quality
thyroid gland	UBERON:0002046	80.98	gold quality
body of uterus	UBERON:0009853	80.73	gold quality
adipose tissue	UBERON:0001013	80.72	gold quality
body of pancreas	UBERON:0001150	80.03	gold quality
ventricular zone	UBERON:0003053	79.77	gold quality
left uterine tube	UBERON:0001303	79.56	gold quality
pancreas	UBERON:0001264	79.43	gold quality
cortex of kidney	UBERON:0001225	79.32	gold quality
kidney	UBERON:0002113	79.22	gold quality
metanephros	UBERON:0000081	79.18	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.13	gold quality
islet of Langerhans	UBERON:0000006	79.03	gold quality
adipose tissue of abdominal region	UBERON:0007808	78.92	gold quality
descending thoracic aorta	UBERON:0002345	78.89	gold quality
adult mammalian kidney	UBERON:0000082	78.88	gold quality
omental fat pad	UBERON:0010414	78.74	gold quality
peritoneum	UBERON:0002358	78.73	gold quality
body of stomach	UBERON:0001161	78.67	gold quality
right lobe of liver	UBERON:0001114	78.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting ZBED3, 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-9-5P	100.00	72.28	2361
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-3620-5P	97.42	63.95	792
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-1256	95.44	66.33	784
HSA-MIR-4804-5P	91.83	65.35	105

Literature-anchored findings (GeneRIF, showing 10)

• Zbed3 is a novel Axin-binding protein that is involved in Wnt/beta-catenin signaling modulation. (PMID:19141611)
• results suggest that the Zbed3 protein may be a cytokine associated with insulin resistance in humans that is influenced by glucose and insulin levels. (PMID:24283382)
• results suggest that Zbed3 may contribute to lung cancer cell invasion through regulating beta-catenin and p120ctn-1 and may be a promissing cancer marker in non-small cell lung cancer (PMID:25263389)
• Zbed3 concentrations were significantly higher in metabolic syndrome patients compared with healthy subjects. Circulating Zbed3 concentrations were associated with glucose and lipid parameters, markers of adiposity, and blood pressure. (PMID:28346859)
• Finally, the wnt-inhibitor DKK1 could reverse the stimulatory effect of ZBED3-AS1 on chondrogenesis. These findings demonstrate the role of a new lncRNA, ZBED3-AS1, in SFMSC chondrogenesis and may improve osteoarthritis treatment. (PMID:28431932)
• Zbed3 enhances lung cancer cell proliferation. (PMID:30417576)
• The function of BED finger domain of Zbed3 in regulating lung cancer cell proliferation. (PMID:30805970)
• Long noncoding RNA ZBED3-AS1 restrains breast cancer progression by targeting the microRNA-513a-5p/KLF6 axis. (PMID:34427978)
• Circular RNA hsa_circ_0119412 contributes to tumorigenesis of gastric cancer via the regulation of the miR-1298-5p/zinc finger BED-type containing 3 (ZBED3) axis. (PMID:35200111)
• RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism. (PMID:38182896)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zbed3	ENSMUSG00000041995
rattus_norvegicus	Zbed3	ENSRNOG00000028941

Protein

Protein identifiers

Zinc finger BED domain-containing protein 3 — Q96IU2 (reviewed: Q96IU2)

Alternative names: Axin-interacting protein

All UniProt accessions (2): D6RIC4, Q96IU2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a positive regulator in the activation of the canonical Wnt/beta-catenin signaling pathway by stabilizing cytoplasmic beta-catenin. Involved in transcription activation of Wnt target gene expression. Plays a role in symmetric division of blastomeres in the early stages of embryogenesis via regulation of mitotic spindle central positioning and organization of the F-actin filament network. Plays a role in regulating the distribution of cellular organelles, via modulation of cytoskeletal dynamics and cytoplasmic lattice formation.

Subunit / interactions. Associates with the subcortical maternal complex (SCMC) composed of at least NLRP5, KHDC3L, OOEP, and TLE6 via interaction with NLRP5 and TLE6. Interacts with AXIN1; the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations.

Subcellular location. Cytoplasm. Membrane. Secreted.

Tissue specificity. Secreted in blood plasma, and expressed in skeletal muscle and adipose tissue (at protein level).

Induction. Induced in blood plasma by hyperglycemia. Decreased in blood plasma by hyperinsulinemia.

RefSeq proteins (2): NP_001316493, NP_115743* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003656	Znf_BED	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR043471	ZBED2/3	Family

Pfam: PF02892

UniProt features (11 total): binding site 4, region of interest 3, compositionally biased region 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96IU2-F1	75.51	0.38

Functional residue map

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

Ligand- & substrate-binding residues (4): 97; 69; 72; 92

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 135 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_SPINDLE_LOCALIZATION, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, MARTINEZ_RB1_TARGETS_DN, GOBP_RESPONSE_TO_INSULIN, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_PROTEIN_STABILIZATION, GOBP_NEGATIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS

GO Biological Process (13): negative regulation of protein phosphorylation (GO:0001933), regulation of transcription by RNA polymerase II (GO:0006357), actin filament organization (GO:0007015), response to glucose (GO:0009749), Wnt signaling pathway (GO:0016055), response to insulin (GO:0032868), positive regulation of embryonic development (GO:0040019), positive regulation of transcription by RNA polymerase II (GO:0045944), protein stabilization (GO:0050821), establishment of spindle localization (GO:0051293), endoplasmic reticulum localization (GO:0051643), mitochondrion localization (GO:0051646), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (4): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), zinc ion binding (GO:0008270), metal ion binding (GO:0046872)

GO Cellular Component (6): chromatin (GO:0000785), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
organelle localization	2
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
regulation of DNA-templated transcription	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
response to hexose	1
cell surface receptor signaling pathway	1
response to peptide hormone	1
embryo development	1
regulation of embryonic development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
positive regulation of DNA-templated transcription	1
regulation of protein stability	1
microtubule cytoskeleton organization	1
establishment of localization in cell	1
spindle localization	1
establishment of organelle localization	1
endoplasmic reticulum organization	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transition metal ion binding	1
cation binding	1
chromosome	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBED3	AXIN1	O15169	736
ZBED3	OOEP	A6NGQ2	735
ZBED3	NLRP5	P59047	721
ZBED3	ZFAND6	Q6FIF0	706
ZBED3	PADI6	Q6TGC4	705
ZBED3	TLE6	Q9H808	689
ZBED3	CDKAL1	Q5VV42	682
ZBED3	HHEX	Q03014	657
ZBED3	IGF2BP2	Q9Y6M1	621
ZBED3	TSPAN8	P19075	619
ZBED3	NLRP2	Q9NX02	585
ZBED3	ARAP1	Q96P48	575
ZBED3	CDC123	O75794	572
ZBED3	FTO	Q9C0B1	559
ZBED3	ZBED6	P86452	545
ZBED3	KLF14	Q8TD94	545

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ZBED3	NLRP7	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
SLC1A2	UBXN8	psi-mi:“MI:0914”(association)	0.350
SLC1A3	DDX11L8	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): ZBED3 (Affinity Capture-MS), ZBED3 (Affinity Capture-MS), ZBED3 (Affinity Capture-MS), ZBED3 (Synthetic Lethality), ZBED3 (Proximity Label-MS), ZBED3 (Affinity Capture-RNA), ZBED3 (Proximity Label-MS), ZBED3 (Proximity Label-MS), ZBED3 (Affinity Capture-MS), ZBED3 (Affinity Capture-MS), ZBED3 (Affinity Capture-MS), ZBED3 (Affinity Capture-RNA), ZBED3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A286YF58, A0A2R8YCJ5, A0A7I2V3R4, A2A699, A2VDX9, A6NCS6, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NLJ0, A8MVW0, B2RU40, B7Z1M9, B8ZZ34, C9JH25, C9JVW0, D4A9R4, J3QNX5, M0QZC1, P03971, P0CG09, P0DPE3, Q0PHV7, Q0VD38, Q14761, Q29RK8, Q29RM6, Q2KJ18, Q2M3G4, Q2M3V2, Q5T442, Q64697, Q69YZ2, Q6F5E0, Q6NY19, Q6UXK2, Q80XF7

Diamond homologs: Q96IU2, Q9BTP6, Q9D0L1, O75132

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

540 predictions. Top by Δscore:

Variant	Effect	Δscore
5:77087109:ACC:A	donor_gain	1.0000
5:77087110:CCC:C	donor_gain	1.0000
5:77078759:A:T	acceptor_gain	0.9900
5:77087109:AC:A	donor_gain	0.9900
5:77087110:CC:C	donor_gain	0.9900
5:77077894:CG:C	acceptor_gain	0.9800
5:77077904:C:CT	acceptor_gain	0.9800
5:77078758:CAG:C	acceptor_gain	0.9800
5:77087103:ACAC:A	donor_loss	0.9800
5:77087104:CACT:C	donor_loss	0.9800
5:77087107:T:TG	donor_loss	0.9800
5:77087108:CACC:C	donor_loss	0.9800
5:77087109:A:AC	donor_gain	0.9800
5:77087110:C:A	donor_loss	0.9800
5:77087110:C:CC	donor_gain	0.9800
5:77077896:C:CC	acceptor_gain	0.9700
5:77077905:A:T	acceptor_gain	0.9700
5:77078729:C:CC	acceptor_gain	0.9700
5:77079227:T:TA	donor_gain	0.9700
5:77077892:CACG:C	acceptor_gain	0.9600
5:77078724:CAGTG:C	acceptor_gain	0.9600
5:77085018:TGG:T	donor_gain	0.9500
5:77077893:ACGC:A	acceptor_loss	0.9300
5:77077897:T:A	acceptor_loss	0.9300
5:77078760:G:GC	acceptor_gain	0.9300
5:77077893:ACG:A	acceptor_gain	0.9200
5:77077894:CGC:C	acceptor_gain	0.9200
5:77087109:ACCC:A	donor_gain	0.9200
5:77087110:CCCC:C	donor_gain	0.9200
5:77078727:TG:T	acceptor_gain	0.9000

AlphaMissense

1468 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:77077723:G:C	F52L	0.998
5:77077723:G:T	F52L	0.998
5:77077725:A:G	F52L	0.998
5:77077724:A:G	F52S	0.996
5:77077732:C:A	W49C	0.993
5:77077732:C:G	W49C	0.993
5:77077603:G:C	H92Q	0.991
5:77077603:G:T	H92Q	0.991
5:77077734:A:G	W49R	0.989
5:77077734:A:T	W49R	0.989
5:77077605:G:C	H92D	0.988
5:77077605:G:T	H92N	0.988
5:77077724:A:C	F52C	0.986
5:77077725:A:T	F52I	0.986
5:77077588:G:C	H97Q	0.982
5:77077588:G:T	H97Q	0.982
5:77077613:A:G	L89S	0.982
5:77077674:A:G	C69R	0.982
5:77077492:C:A	W129C	0.980
5:77077492:C:G	W129C	0.980
5:77077590:G:C	H97D	0.980
5:77077673:C:T	C69Y	0.980
5:77077609:C:A	W90C	0.976
5:77077609:C:G	W90C	0.976
5:77077725:A:C	F52V	0.976
5:77077601:A:T	L93Q	0.975
5:77077661:C:A	G73V	0.975
5:77077664:C:T	C72Y	0.975
5:77077673:C:G	C69S	0.975
5:77077674:A:T	C69S	0.975

dbSNP variants (sampled 300 via entrez): RS1000135858 (5:77088635 C>CT), RS1000188611 (5:77088903 A>G), RS1000412859 (5:77081871 A>C), RS1000801034 (5:77084009 A>T), RS1000870471 (5:77082303 T>C), RS1001099631 (5:77076008 T>A,C), RS1001580088 (5:77080787 C>A,T), RS1001638736 (5:77087559 G>A,T), RS1001730317 (5:77087201 C>T), RS1001859751 (5:77082676 G>A,C), RS1001926127 (5:77081026 C>T), RS1001960 (5:77075294 T>A,C), RS1001973871 (5:77089019 G>T), RS1001990319 (5:77072120 G>T), RS1002072711 (5:77088796 A>G)

Disease associations

OMIM: gene MIM:615250 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000712_1	Type 2 diabetes	3.000000e-12
GCST004894_129	Type 2 diabetes	5.000000e-10
GCST004894_54	Type 2 diabetes	9.000000e-11
GCST005047_47	Type 2 diabetes	5.000000e-11
GCST005047_97	Type 2 diabetes	3.000000e-10
GCST009379_38	Type 2 diabetes	8.000000e-18

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	8
Aflatoxin B1	affects expression, decreases expression	3
sodium arsenite	decreases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
2-butenal	decreases expression	1
butyraldehyde	decreases expression	1
ferrous chloride	decreases expression	1
cupric chloride	decreases expression	1
avobenzone	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	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	decreases expression	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Phenobarbital	affects expression	1
Quercetin	decreases expression	1
Dronabinol	increases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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