DTX2

Summary

DTX2 (deltex E3 ubiquitin ligase 2, HGNC:15973) is a protein-coding gene on chromosome 7q11.23, encoding Probable E3 ubiquitin-protein ligase DTX2 (Q86UW9). Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations.

DTX2 functions as an E3 ubiquitin ligase (Takeyama et al., 2003 [PubMed 12670957]).

Source: NCBI Gene 113878 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 140 total
• MANE Select transcript: NM_001102594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15973
Approved symbol	DTX2
Name	deltex E3 ubiquitin ligase 2
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	RNF58, KIAA1528
Ensembl gene	ENSG00000091073
Ensembl biotype	protein_coding
OMIM	613141
Entrez	113878

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 41 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000324432, ENST00000413936, ENST00000423646, ENST00000425780, ENST00000429179, ENST00000430490, ENST00000435251, ENST00000435861, ENST00000438930, ENST00000442516, ENST00000446600, ENST00000446820, ENST00000451769, ENST00000456590, ENST00000457529, ENST00000465488, ENST00000467729, ENST00000468546, ENST00000472426, ENST00000479915, ENST00000492339, ENST00000899001, ENST00000899002, ENST00000899003, ENST00000899004, ENST00000899005, ENST00000899006, ENST00000899007, ENST00000899008, ENST00000899009, ENST00000899010, ENST00000899011, ENST00000899012, ENST00000899013, ENST00000899014, ENST00000899015, ENST00000899016, ENST00000899017, ENST00000899018, ENST00000920551, ENST00000920552, ENST00000920553, ENST00000920554, ENST00000944733, ENST00000944734, ENST00000944735, ENST00000944736, ENST00000944737

RefSeq mRNA: 4 — MANE Select: NM_001102594 NM_001102594, NM_001102595, NM_001102596, NM_020892

CCDS: CCDS43605, CCDS5587

Canonical transcript exons

ENST00000430490 — 11 exons

Exon	Start	End
ENSE00000369924	76497337	76497477
ENSE00001146263	76463545	76463709
ENSE00001755686	76461709	76461836
ENSE00002721179	76492153	76492253
ENSE00003459592	76500441	76500520
ENSE00003536826	76502298	76502456
ENSE00003572603	76482508	76483147
ENSE00003578695	76505374	76505991
ENSE00003639247	76480421	76480777
ENSE00003658954	76504356	76504445
ENSE00003679979	76503426	76503587

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.06.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.06	gold quality
esophagus mucosa	UBERON:0002469	95.59	gold quality
mucosa of transverse colon	UBERON:0004991	94.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.40	gold quality
sural nerve	UBERON:0015488	94.04	gold quality
right testis	UBERON:0004534	93.99	gold quality
minor salivary gland	UBERON:0001830	93.59	gold quality
left testis	UBERON:0004533	93.55	gold quality
blood	UBERON:0000178	93.31	gold quality
saliva-secreting gland	UBERON:0001044	92.98	gold quality
testis	UBERON:0000473	92.62	gold quality
skin of leg	UBERON:0001511	92.22	gold quality
zone of skin	UBERON:0000014	92.13	gold quality
skin of abdomen	UBERON:0001416	91.90	gold quality
vagina	UBERON:0000996	91.51	gold quality
right uterine tube	UBERON:0001302	91.12	gold quality
esophagus	UBERON:0001043	90.27	gold quality
granulocyte	CL:0000094	90.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.85	gold quality
transverse colon	UBERON:0001157	89.04	gold quality
tonsil	UBERON:0002372	89.04	gold quality
prostate gland	UBERON:0002367	89.01	gold quality
spleen	UBERON:0002106	88.92	gold quality
uterine cervix	UBERON:0000002	88.33	gold quality
ectocervix	UBERON:0012249	87.88	gold quality
body of stomach	UBERON:0001161	87.57	gold quality
fundus of stomach	UBERON:0001160	87.51	gold quality
colonic epithelium	UBERON:0000397	87.29	gold quality
endocervix	UBERON:0000458	87.03	gold quality
stomach	UBERON:0000945	87.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting DTX2, 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-4500	99.99	72.72	2367
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-3943	95.87	64.57	523

Literature-anchored findings (GeneRIF, showing 3)

• It is reported that BBAP and the human family of DTX proteins (DTX1, DTX2, and DTX3) function as E3 ligases based on their capacity for self-ubiquitination. (PMID:12670957)
• DTX2 is a gene encoding a WWE-RING-finger protein and involved in regulating heart development and heart functions. (PMID:17286044)
• [DTX2 overexpression promotes migration and invasion of colorectal cancer cells through the Notch2/Akt axis]. (PMID:37087577)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dtx2	ENSDARG00000032933
mus_musculus	Dtx2	ENSMUSG00000004947
rattus_norvegicus	Dtx2	ENSRNOG00000001432

Paralogs (4): DTX4 (ENSG00000110042), DTX1 (ENSG00000135144), DTX3L (ENSG00000163840), DTX3 (ENSG00000178498)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase DTX2 — Q86UW9 (reviewed: Q86UW9)

Alternative names: Protein deltex-2, RING finger protein 58, RING-type E3 ubiquitin transferase DTX2

All UniProt accessions (11): Q86UW9, C9IYX1, C9JEH4, C9JF39, C9JII1, C9JLU8, C9JS11, C9JVC8, C9JY61, E7ET89, H7C3B8

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Functions as a ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity.

Subunit / interactions. Homodimer. May form a heterodimer with other members of the Deltex family. Interacts with NOTCH1.

Subcellular location. Cytoplasm. Nucleus.

Domain organisation. The WWE domains are thought to mediate some protein-protein interaction, and are frequently found in ubiquitin ligases.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the Deltex family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86UW9-1	1, A	yes
Q86UW9-2	2, B

RefSeq proteins (4): NP_001096064, NP_001096065, NP_001096066, NP_065943 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR004170	WWE_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018123	WWE-dom_subgr	Domain
IPR037197	WWE_dom_sf	Homologous_superfamily
IPR039396	Deltex_C	Domain
IPR039398	Deltex_fam	Family
IPR039399	Deltex_C_sf	Homologous_superfamily

Pfam: PF02825, PF18102

UniProt features (45 total): strand 13, turn 8, modified residue 6, helix 5, sequence variant 3, compositionally biased region 3, domain 2, region of interest 2, chain 1, splice variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6Y2X	X-RAY DIFFRACTION	1.77
6Y22	X-RAY DIFFRACTION	2.07
6Y3J	X-RAY DIFFRACTION	2.6
6IR0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UW9-F1	73.01	0.52

Functional residue map

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

Post-translational modifications (6): 215, 233, 249, 256, 360, 213

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus

MSigDB gene sets: 165 (showing top): REACTOME_SIGNALING_BY_NOTCH, AP1_01, TGCGCANK_UNKNOWN, TAL1ALPHAE47_01, TGCTGAY_UNKNOWN, BACH2_01, TGANTCA_AP1_C, SHIN_B_CELL_LYMPHOMA_CLUSTER_2, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, NRF2_Q4, NRF2_01, chr7q11, NFE2_01, TAL1BETAE47_01, AP1FJ_Q2

GO Biological Process (2): Notch signaling pathway (GO:0007219), protein ubiquitination (GO:0016567)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear membrane (GO:0031965), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by NOTCH1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
nucleus	1
nuclear envelope	1
organelle membrane	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTX2	RFX6	Q8HWS3	865
DTX2	SS18L1	O75177	746
DTX2	RFX3	P48380	731
DTX2	CCNK	O75909	720
DTX2	ANK2	Q01484	713
DTX2	ANK1	P16157	709
DTX2	ANK3	Q12955	709
DTX2	RFX2	P48378	581
DTX2	RFX4	Q33E94	549
DTX2	NEUROG3	Q9Y4Z2	548
DTX2	VPS9D1	Q9Y2B5	500
DTX2	PPY	P01298	498
DTX2	OBSL1	O75147	437
DTX2	RNF146	Q9NTX7	417
DTX2	DDX39A	O00148	401

IntAct

507 interactions, top by confidence:

A	B	Type	Score
DTX2	UBE2D4	psi-mi:“MI:0915”(physical association)	0.880
UBE2D4	DTX2	psi-mi:“MI:0915”(physical association)	0.880
DTX2	NCS1	psi-mi:“MI:0915”(physical association)	0.830
DTX2	ALKBH4	psi-mi:“MI:0915”(physical association)	0.830
ALKBH4	DTX2	psi-mi:“MI:0915”(physical association)	0.830
NCS1	DTX2	psi-mi:“MI:0915”(physical association)	0.830
DTX2	NCALD	psi-mi:“MI:0915”(physical association)	0.800
NCALD	DTX2	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (435): DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid), DTX2 (Two-hybrid)

ESM2 similar proteins: A0A5F9C6I2, A2BDA5, A4IG66, A4IIM9, A9ZLX4, D3ZXK7, O00750, O14525, O15105, O15169, O15259, O15360, O35253, O54828, O70240, O88406, O88566, P49805, Q1JPG0, Q3B7M3, Q3SZD5, Q5JV73, Q5T011, Q5XJS0, Q5XPI3, Q61137, Q62925, Q66K64, Q6AYG1, Q6P1H6, Q6P2E9, Q6PFH3, Q7L4E1, Q7TP65, Q86UW9, Q86XL3, Q8BK03, Q8CDG3, Q8CF97, Q8N9B5

Diamond homologs: A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4F6W9, B8N7E5, C6KTB7, E1B7Q7, F1LP64, F1RCR6, G5E870, O00308, O13834, O14326, O15033, P33202, P40985, Q0CCL1, Q14669, Q15386, Q2TAS2, Q2UBP1, Q4WTF3, Q5BDP1, Q61010, Q6PDK8, Q757T0, Q80U95, Q86UW9, Q86Y01, Q8AW93, Q8BZZ3, Q8C863, Q8CHG5, Q8R3P2, Q96J02, Q9DBH0, Q9H0M0, Q9HAU4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	DTX2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Antigen processing: Ubiquitination & Proteasome degradation	5	7.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of signal transduction	6	36.5×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2545 predictions. Top by Δscore:

Variant	Effect	Δscore
7:76477079:G:GT	donor_gain	1.0000
7:76480775:CCGG:C	donor_loss	1.0000
7:76480776:CGGT:C	donor_loss	1.0000
7:76480777:GGTA:G	donor_loss	1.0000
7:76480778:G:GC	donor_loss	1.0000
7:76480779:T:G	donor_loss	1.0000
7:76482506:A:AG	acceptor_gain	1.0000
7:76482506:AG:A	acceptor_gain	1.0000
7:76482507:G:GA	acceptor_gain	1.0000
7:76482507:G:T	acceptor_loss	1.0000
7:76482507:GG:G	acceptor_gain	1.0000
7:76482507:GGC:G	acceptor_gain	1.0000
7:76482507:GGCA:G	acceptor_gain	1.0000
7:76482507:GGCAC:G	acceptor_gain	1.0000
7:76492151:A:AG	acceptor_gain	1.0000
7:76492152:G:GG	acceptor_gain	1.0000
7:76502296:A:AG	acceptor_gain	1.0000
7:76502297:G:GG	acceptor_gain	1.0000
7:76502449:GCAA:G	donor_gain	1.0000
7:76503585:CAGG:C	donor_loss	1.0000
7:76503588:GTGAG:G	donor_loss	1.0000
7:76504350:CCGCA:C	acceptor_loss	1.0000
7:76504351:CGCAG:C	acceptor_loss	1.0000
7:76504352:GCA:G	acceptor_loss	1.0000
7:76504353:CAGG:C	acceptor_loss	1.0000
7:76504354:A:AG	acceptor_gain	1.0000
7:76504354:A:G	acceptor_loss	1.0000
7:76504354:AG:A	acceptor_gain	1.0000
7:76504355:G:GG	acceptor_gain	1.0000
7:76504355:GG:G	acceptor_gain	1.0000

AlphaMissense

4046 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:76502301:T:C	C412R	1.000
7:76502303:C:G	C412W	1.000
7:76502424:T:C	C453R	1.000
7:76502426:C:G	C453W	1.000
7:76503441:T:A	C469S	1.000
7:76503441:T:C	C469R	1.000
7:76503442:G:C	C469S	1.000
7:76504401:T:C	F533L	1.000
7:76504403:T:A	F533L	1.000
7:76504403:T:G	F533L	1.000
7:76504420:T:C	L539P	1.000
7:76505411:T:C	L560P	1.000
7:76505416:T:C	F562L	1.000
7:76505417:T:C	F562S	1.000
7:76505418:C:A	F562L	1.000
7:76505418:C:G	F562L	1.000
7:76505464:T:A	W578R	1.000
7:76505464:T:C	W578R	1.000
7:76505466:G:C	W578C	1.000
7:76505466:G:T	W578C	1.000
7:76505484:G:C	K584N	1.000
7:76505484:G:T	K584N	1.000
7:76505558:T:C	L609P	1.000
7:76480573:T:A	W22R	0.999
7:76480573:T:C	W22R	0.999
7:76480575:G:C	W22C	0.999
7:76480575:G:T	W22C	0.999
7:76480739:T:A	I77N	0.999
7:76502302:G:A	C412Y	0.999
7:76502302:G:T	C412F	0.999

dbSNP variants (sampled 300 via entrez): RS1000130029 (7:76483793 C>T), RS1000325454 (7:76465079 C>G), RS1000603294 (7:76483583 G>A,C), RS1000930599 (7:76469032 T>G), RS1000978791 (7:76479403 A>C,G), RS1001010088 (7:76478670 C>A), RS1001169189 (7:76489981 C>G,T), RS1001256708 (7:76469559 A>C), RS1001357618 (7:76503300 G>A,T), RS1001536844 (7:76490978 G>A,C), RS1001812967 (7:76478434 G>A,T), RS1001858343 (7:76472576 C>A,G), RS1001924934 (7:76472102 A>G), RS1001986349 (7:76480863 G>A,C), RS1002141144 (7:76495436 T>A,C)

Disease associations

OMIM: gene MIM:613141 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	2
Air Pollutants	affects expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	affects methylation	1
beta-methylcholine	affects expression	1
enzalutamide	affects expression	1
Sunitinib	increases expression	1
Arsenic	decreases expression, increases abundance	1
Ethyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7NV	Ubigene A-549 DTX2 KO	Cancer cell line	Male
CVCL_D8KA	Ubigene HCT 116 DTX2 KO	Cancer cell line	Male
CVCL_D9DM	Ubigene HEK293 DTX2 KO	Transformed cell line	Female
CVCL_E0BV	Ubigene HeLa DTX2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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