DVL2

Summary

DVL2 (dishevelled segment polarity protein 2, HGNC:3086) is a protein-coding gene on chromosome 17p13.1, encoding Segment polarity protein dishevelled homolog DVL-2 (O14641). Plays a role in the signal transduction pathways mediated by multiple Wnt genes.

This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans.

Source: NCBI Gene 1856 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Robinow syndrome (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 137 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_004422

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3086
Approved symbol	DVL2
Name	dishevelled segment polarity protein 2
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000004975
Ensembl biotype	protein_coding
OMIM	602151
Entrez	1856

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 9 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000005340, ENST00000571745, ENST00000572285, ENST00000573354, ENST00000574143, ENST00000574591, ENST00000574642, ENST00000575086, ENST00000575458, ENST00000575756, ENST00000576285, ENST00000576439, ENST00000576840, ENST00000576949, ENST00000577154, ENST00000904799, ENST00000930218, ENST00000930219, ENST00000930220, ENST00000930221, ENST00000930222, ENST00000930223, ENST00000951245, ENST00000951246, ENST00000951247

RefSeq mRNA: 1 — MANE Select: NM_004422 NM_004422

CCDS: CCDS11091

Canonical transcript exons

ENST00000005340 — 15 exons

Exon	Start	End
ENSE00000887269	7226421	7226639
ENSE00001061609	7225342	7226313
ENSE00001282182	7227090	7227269
ENSE00001282226	7229378	7229447
ENSE00001296084	7234069	7234517
ENSE00003466284	7230046	7230155
ENSE00003505717	7230285	7230430
ENSE00003570184	7230728	7230797
ENSE00003585779	7229808	7229943
ENSE00003619673	7227404	7227535
ENSE00003668239	7229588	7229678
ENSE00003681382	7227655	7227783
ENSE00003687191	7229135	7229274
ENSE00003694443	7228969	7229045
ENSE00003783997	7227977	7228044

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 94.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3394 / max 79.9423, expressed in 1788 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164155	8.8157	1754
164152	2.4242	1258
164153	1.9747	1030
164156	0.6833	451
164154	0.4415	209

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	94.61	gold quality
stromal cell of endometrium	CL:0002255	94.56	gold quality
left ovary	UBERON:0002119	93.85	gold quality
ectocervix	UBERON:0012249	93.85	gold quality
right ovary	UBERON:0002118	93.66	gold quality
body of uterus	UBERON:0009853	93.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.52	gold quality
lower esophagus mucosa	UBERON:0035834	93.42	gold quality
endocervix	UBERON:0000458	93.23	gold quality
adenohypophysis	UBERON:0002196	93.12	gold quality
ganglionic eminence	UBERON:0004023	93.07	gold quality
right adrenal gland cortex	UBERON:0035827	93.06	gold quality
vagina	UBERON:0000996	93.02	gold quality
pituitary gland	UBERON:0000007	92.75	gold quality
ovary	UBERON:0000992	92.71	gold quality
cerebellar hemisphere	UBERON:0002245	92.66	gold quality
right adrenal gland	UBERON:0001233	92.65	gold quality
cerebellar cortex	UBERON:0002129	92.52	gold quality
cervix squamous epithelium	UBERON:0006922	92.43	silver quality
right uterine tube	UBERON:0001302	92.42	gold quality
skin of leg	UBERON:0001511	91.86	gold quality
right lobe of thyroid gland	UBERON:0001119	91.35	gold quality
left lobe of thyroid gland	UBERON:0001120	91.11	gold quality
cerebellum	UBERON:0002037	91.09	gold quality
left adrenal gland	UBERON:0001234	91.07	gold quality
left adrenal gland cortex	UBERON:0035825	91.04	gold quality
skin of abdomen	UBERON:0001416	91.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.93	gold quality
lower esophagus	UBERON:0013473	90.91	gold quality
metanephros cortex	UBERON:0010533	90.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

43 targeting DVL2, 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-3163	100.00	77.23	8605
HSA-MIR-4673	100.00	66.64	1490
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-6507-3P	99.35	67.32	1059

Literature-anchored findings (GeneRIF, showing 40)

• DACT1 antagonizes Wnt signaling by promoting DVL2 degradation. (PMID:16446366)
• The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. (PMID:17529994)
• These data provide evidence that there is a novel signaling pathway from Dishevelled to p53. (PMID:17593335)
• The expression of Dishevelleds in mammalian cells provide an estimate of the relative cellular abundance of each Dvl. (PMID:18093802)
• Expression of Dvl-1, Dvl-2 and Dvl-3, is common in non-small cell lung cancer (PMID:18692936)
• BAMBI interacts with Wnt receptor Frizzled5, coreceptor LRP6, and Dishevelled2 and increases the interaction between Frizzled5 and Dishevelled2 (PMID:18838381)
• The canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of beta-catenin. (PMID:20137080)
• A novel function of Dishevelled protein in modulating NF-kappaB-regulated gene transcription. (PMID:20628365)
• Binding of Dvl2 to p62 facilitates the aggregation and the LC3-mediated autophagosome recruitment of Dvl2 under starvation; the ubiquitylated Dvl2 aggregates are ultimately degraded through the autophagy-lysosome pathway. (PMID:20639871)
• These results suggested that Dvl2 is involved in mitotic progression by regulating the dynamics of MT plus-ends and the SAC in Plk1-dependent and -independent manners. (PMID:20823832)
• up-regulation of DVL2 is associated with androgen-independent prostate carcinoma (PMID:21487968)
• identification of a leucine-rich binding motif strongly resembling the consensus sequence of a nuclear export signal in human Dishevelled-2 using C-terminal phage display (PMID:21666888)
• Dishevelled 2 (Dvl2), a key component of the Wnt signaling pathway, is overexpressed in human gliomas. (PMID:21990322)
• These findings identify a role for beta-arrestin and Dvl-2 scaffolds in APC-activated PAR1 cytoprotective signaling in human endothelial cells. (PMID:22106258)
• Our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease. (PMID:22223637)
• Identification of a novel Wnt5a-CK1varepsilon-Dvl2-Plk1-mediated primary cilia disassembly pathway. (PMID:22609948)
• Wnt5a promotes breast cancer cell migration via Dvl2/Daam1/RhoA. (PMID:22655072)
• Overexpression of ITCH inhibited wild-type DVL2 -induced, but not DVL2-Y568F mutant-induced, Wnt reporter activity. (PMID:22826439)
• Both single-marker and haplotype analyses showed an association between SNPs in the DVL2 gene and the risk for cleft lip with or without cleft palate. (PMID:22887353)
• In a cohort of patients with neural tube defects but not in controls, 5 rare mutations were found.p.Tyr667Cys & p.Ala53Val were predicted to be harmful. A patient with caudal agenesis had a 1-bp insertion (c.1801_1802insG) in exon 15. (PMID:22892949)
• Dvl2 protein transduce signals via the Wnt proteins non canonical pathways, namely via NFAT protein and Src kinase and novel NPM-ALK interacting proteins and possibly NPM-ALK substrates. (PMID:23022960)
• RIPK4 interacted constitutively with the adaptor protein DVL2; phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling (PMID:23371553)
• Wnt-induced dishevelled 2 phosphorylation has effects in in canonical and noncanonical Wnt3a and Wnt5a signaling (PMID:23396967)
• site-specific Dvl2 phosphorylation is required for Dvl2 association with PKCiota; this interaction is likely to be one of the mechanisms essential for Wnt3a-dependent neurite outgrowth (PMID:23396968)
• NEDD4L is able to directly bind Dvl2 and target Dvl2 for proteasomal degradation. (PMID:23396981)
• Dvl2 knockdown in LNCaP cells reduces malignant cell behavior by suppressing Wnt-3a signaling and MMP activity. (PMID:23652996)
• High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-beta and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner. (PMID:24427302)
• IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2. (PMID:24616100)
• these results indicate that RNF185 negatively regulates osteogenesis through the degradation of Dvl2 and down-regulation of canonical Wnt signaling pathway and suggest a possible therapeutic target in osteoporosis. (PMID:24727453)
• Elevated DVL2 expression is associated with drug resistance in colorectal cancer. (PMID:24893630)
• The data suggest that the expression of DVL2 in colon tissue segments may be important in the pathogenesis of HSCR. (PMID:25395054)
• The interaction of Dvl2 with Dapper-1 is involved in the negative regulation of Wnt signaling. (PMID:25558878)
• APPL1 is a positive regulator of Dvl2-dependent transcriptional activity of AP-1. (PMID:25622892)
• Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregate-elicited autophagy initiation (PMID:25825496)
• Epsins are required for Dishevelled stability and Wnt signalling activation in colon cancer development. (PMID:25871009)
• In pancreatic cancer cells, AF6 is expressed at reduced levels, causing Dvl2 to be upregulated and available to bind and enhance FOXE1-induced trans-activation of Snail, which promotes proliferation and metastasis. (PMID:26013125)
• ESCC patients with high Dvl2 expression had worse prognoses and multivariate analysis indicated that Dvl2 was an independent risk factor for ESCC patients’ survival. Our clinical data indicated that Dvl2 contribute to the malignant progression of ESCC and might be a prognostic biomarker. (PMID:27083564)
• Data show that dishevelled proteins DVL1, 2 and 3 were exclusively expressed in chronic lymphatic leukaemia (CLL) cells as compared to normal peripheral blood mononuclear cells (PBMCs). (PMID:27086035)
• inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/beta-catenin signaling. (PMID:27432651)
• The secreted frizzled-related protein and disheveled protein family members appear to be actively involved in the pathogenesis of primary testicular germ cell tumors. (PMID:27599467)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dvl2	ENSDARG00000056184
mus_musculus	Dvl2	ENSMUSG00000020888
rattus_norvegicus	Dvl2	ENSRNOG00000017915
drosophila_melanogaster	dsh	FBGN0000499
caenorhabditis_elegans		WBGENE00001101
caenorhabditis_elegans		WBGENE00001102
caenorhabditis_elegans		WBGENE00003241

Paralogs (3): DVL1 (ENSG00000107404), DIXDC1 (ENSG00000150764), DVL3 (ENSG00000161202)

Protein

Protein identifiers

Segment polarity protein dishevelled homolog DVL-2 — O14641 (reviewed: O14641)

Alternative names: DSH homolog 2

All UniProt accessions (5): O14641, I3L0M7, I3L0Z8, I3L2N2, I3L2W9

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the signal transduction pathways mediated by multiple Wnt genes. Participates both in canonical and non-canonical Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Promotes internalization and degradation of frizzled proteins upon Wnt signaling.

Subunit / interactions. Interacts through its PDZ domain with the C-terminal regions of VANGL1 and VANGL2. Interacts with Rac. Interacts with ARRB1; the interaction is enhanced by phosphorylation of DVL1. Can form large oligomers (via DIX domain). Interacts (via DIX domain) with DIXDC1 (via DIX domain). Interacts (via DEP domain) with AP2M1 and the AP-2 complex. Interacts with DACT1 and FAM105B/otulin. Interacts with DCDC2. Interacts (when phosphorylated) with FOXK1 and FOXK2; the interaction induces DVL2 nuclear translocation. Interacts with MAPK15. Interacts with PKD1 (via extracellular domain). Interacts with LMBR1L. Interacts with IRS1 and IRS2; these interactions decrease ‘Lys-63’-linked ubiquitination of DVL2 and stabilize DVL2 protein via suppressing its autophagy-mediated degradation.

Subcellular location. Cell membrane. Cytoplasm. Cytosol. Cytoplasmic vesicle. Nucleus.

Post-translational modifications. Phosphorylated by CSNK1D. WNT3A induces DVL2 phosphorylation by CSNK1E and MARK kinases. Ubiquitinated via ‘Lys-63’-linked polyubiquitin chains; leading to its autophagy-mediated degradation.

Domain organisation. The DIX domain mediates homooligomerization.

Similarity. Belongs to the DSH family.

RefSeq proteins (1): NP_004413* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR001158	DIX	Domain
IPR001478	PDZ	Domain
IPR003351	Dishevelled_protein_dom	Domain
IPR008339	Dishevelled_fam	Family
IPR008341	DVL2	Family
IPR015506	Dsh/Dvl-rel	Family
IPR024580	Dishevelled_C-dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR038207	DIX_dom_sf	Homologous_superfamily

Pfam: PF00595, PF00610, PF00778, PF02377, PF12316

UniProt features (63 total): mutagenesis site 21, strand 16, compositionally biased region 8, helix 7, domain 3, region of interest 3, turn 2, chain 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
3CBZ	X-RAY DIFFRACTION	1.38
3CBY	X-RAY DIFFRACTION	1.5
2REY	X-RAY DIFFRACTION	1.55
6IW3	X-RAY DIFFRACTION	1.64
3CBX	X-RAY DIFFRACTION	1.7
3CC0	X-RAY DIFFRACTION	1.75
8WWR	X-RAY DIFFRACTION	1.75
5SUZ	X-RAY DIFFRACTION	1.84
5SUY	X-RAY DIFFRACTION	1.88
5LNP	X-RAY DIFFRACTION	1.99
4WIP	X-RAY DIFFRACTION	2.69
8YR7	X-RAY DIFFRACTION	3
6JCK	X-RAY DIFFRACTION	3.09
8WMA	ELECTRON MICROSCOPY	3.47
8WM9	ELECTRON MICROSCOPY	3.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14641-F1	59.37	0.18

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 (1): 211

Mutagenesis-validated functional residues (21):

Position	Phenotype
250–252	almost abolishes interaction with foxk2.
250	no effect on interaction with foxk2.
251	no effect on interaction with foxk2.
252	almost abolishes interaction with foxk2.
254–257	almost abolishes interaction with foxk2.
254	reduces interaction with foxk2.
255	almost abolishes interaction with foxk2.
257	almost abolishes interaction with foxk2.
259–262	almost abolishes interaction with foxk2.
259	almost abolishes interaction with foxk2.
260	no effect on interaction with foxk2.
262	almost abolishes interaction with foxk2.
267–269	almost abolishes interaction with foxk2.
267	almost abolishes interaction with foxk2.
269	almost abolishes interaction with foxk2.
275	no effect on interaction with foxk2.
281	no effect on interaction with foxk2.
286	no effect on interaction with foxk2.
295	no effect on interaction with foxk2.
298	no effect on interaction with foxk2.
329	no effect on interaction with foxk2.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-201688	WNT mediated activation of DVL
R-HSA-2028269	Signaling by Hippo
R-HSA-4086400	PCP/CE pathway
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641258	Degradation of DVL
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5099900	WNT5A-dependent internalization of FZD4
R-HSA-5368598	Negative regulation of TCF-dependent signaling by DVL-interacting proteins
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9673324	WNT5:FZD7-mediated leishmania damping

MSigDB gene sets: 277 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, TGCGCANK_UNKNOWN, CMYB_01, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, CACCAGC_MIR138, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM

GO Biological Process (24): neural tube closure (GO:0001843), heart looping (GO:0001947), outflow tract morphogenesis (GO:0003151), regulation of DNA-templated transcription (GO:0006355), small GTPase-mediated signal transduction (GO:0007264), segment specification (GO:0007379), heart development (GO:0007507), intracellular protein localization (GO:0008104), convergent extension involved in neural plate elongation (GO:0022007), regulation of actin cytoskeleton organization (GO:0032956), non-canonical Wnt signaling pathway (GO:0035567), regulation of cell population proliferation (GO:0042127), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), cochlea morphogenesis (GO:0090103), positive regulation of neuron projection arborization (GO:0150012), positive regulation of signal transduction by p53 class mediator (GO:1901798), heart morphogenesis (GO:0003007), Wnt signaling pathway (GO:0016055), segmentation (GO:0035282), intracellular signal transduction (GO:0035556), convergent extension involved in organogenesis (GO:0060029)

GO Molecular Function (7): frizzled binding (GO:0005109), protein kinase binding (GO:0019901), protein domain specific binding (GO:0019904), protein-macromolecule adaptor activity (GO:0030674), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (13): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), aggresome (GO:0016235), lateral plasma membrane (GO:0016328), nuclear body (GO:0016604), cytoplasmic vesicle (GO:0031410), apical part of cell (GO:0045177), clathrin-coated endocytic vesicle (GO:0045334), plasma membrane (GO:0005886), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	4
PCP/CE pathway	2
Signaling by WNT	1
Signal Transduction	1
Beta-catenin independent WNT signaling	1
RHO GTPase Effectors	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Killing mechanisms	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	3
Wnt signaling pathway	2
cytoplasm	2
primary neural tube formation	1
tube closure	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
heart morphogenesis	1
anatomical structure morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular signaling cassette	1
pattern specification process	1
segmentation	1
animal organ development	1
circulatory system development	1
macromolecule localization	1
neural plate elongation	1
convergent extension involved in gastrulation	1
convergent extension involved in organogenesis	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
cell population proliferation	1
regulation of cellular process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
non-canonical Wnt signaling pathway	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
positive regulation of cell projection organization	1
positive regulation of developmental process	1
neuron projection arborization	1

Protein interactions and networks

STRING

2311 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DVL2	LRP6	O75581	981
DVL2	AXIN1	O15169	938
DVL2	FZD4	Q9ULV1	919
DVL2	ARRB2	P32121	907
DVL2	VANGL2	Q9ULK5	901
DVL2	FZD7	O75084	889
DVL2	WNT5A	P41221	888
DVL2	VANGL1	Q8TAA9	887
DVL2	FZD2	Q14332	861
DVL2	FZD5	Q13467	847
DVL2	PLK1	P53350	836
DVL2	WNT3A	P56704	823
DVL2	ARRB1	P49407	811
DVL2	FZD8	Q9H461	802
DVL2	DACT1	Q9NYF0	801

IntAct

468 interactions, top by confidence:

A	B	Type	Score
DVL2	TP53	psi-mi:“MI:0915”(physical association)	0.780
DVL2	DVL2	psi-mi:“MI:0915”(physical association)	0.680
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
TIFA	DVL2	psi-mi:“MI:0915”(physical association)	0.620
DVL2	KLHL12	psi-mi:“MI:0915”(physical association)	0.620
DVL2	TIFA	psi-mi:“MI:0915”(physical association)	0.620
MHR1	DVL2	psi-mi:“MI:0915”(physical association)	0.610
DVL2	MHR1	psi-mi:“MI:0915”(physical association)	0.610
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
DVL2	RIPK4	psi-mi:“MI:0915”(physical association)	0.600
DVL2	RIPK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
AXIN1	DVL2	psi-mi:“MI:0407”(direct interaction)	0.590
DVL2		psi-mi:“MI:0915”(physical association)	0.560
DVL2	RPL9A	psi-mi:“MI:0915”(physical association)	0.560
DVL2	EST1	psi-mi:“MI:0915”(physical association)	0.560
TRX3	DVL2	psi-mi:“MI:0915”(physical association)	0.560
DVL2	GCD7	psi-mi:“MI:0915”(physical association)	0.560
SOF1	DVL2	psi-mi:“MI:0915”(physical association)	0.560
MUD2	DVL2	psi-mi:“MI:0915”(physical association)	0.560
DVL2	SMP1	psi-mi:“MI:0915”(physical association)	0.560
DVL2	RGD1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (776): WWTR1 (Affinity Capture-Western), DVL2 (Affinity Capture-Western), DVL2 (Affinity Capture-MS), DVL2 (Affinity Capture-MS), PCBD1 (Two-hybrid), USP5 (Two-hybrid), POLI (Two-hybrid), CCDC33 (Two-hybrid), DPPA2 (Two-hybrid), DVL2 (Affinity Capture-MS), DVL2 (Two-hybrid), MCRS1 (Two-hybrid), ARHGEF39 (Two-hybrid), DVL2 (Two-hybrid), U2AF2 (Two-hybrid)

ESM2 similar proteins: A0A0G2K2P5, B1WAP7, O14640, O14641, O35927, O60716, O75069, O75122, O97758, P39447, P50636, P51140, P51141, P51142, P54792, Q05AS8, Q06455, Q07157, Q0V989, Q2VJ60, Q4VGL6, Q5F3B1, Q5IS48, Q5R585, Q60838, Q61062, Q61909, Q62136, Q62728, Q6DKE2, Q6NRE7, Q6NUC6, Q6NYW6, Q7KW14, Q7PQ25, Q80X66, Q8BRT1, Q8CID0, Q8VHI6, Q920B0

Diamond homologs: A0A8C0TYJ0, B1WAP7, G5ECY0, O14640, O14641, O15018, O15169, O35625, O35889, O42400, O54824, O55164, O70239, O70240, O75970, O88566, P31007, P31016, P51140, P51141, P51142, P54792, P55196, P57094, P57105, P70175, P78352, Q05AS8, Q12923, Q12959, Q14005, Q155Q3, Q15700, Q22227, Q28C55, Q2VUH7, Q3T0C9, Q5IS48, Q5PYH5, Q5PYH6

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
FZD4	“up-regulates activity”	DVL2	binding
RYK	up-regulates	DVL2	binding
DACT1	down-regulates	DVL2	binding
DVL2	“up-regulates activity”	AXIN1	binding
DVL2	“up-regulates activity”	DVL2	binding
ANKRD6	up-regulates	DVL2	binding
PLK1	up-regulates	DVL2	phosphorylation
CSNK1E	up-regulates	DVL2	phosphorylation
CSNK1D	up-regulates	DVL2	phosphorylation
DVL2	up-regulates	PARD6A	binding
SDC4	up-regulates	DVL2	binding
DVL2	up-regulates	GSK3B/Axin/APC	binding
BAMBI	up-regulates	DVL2	binding
FZD1	“up-regulates activity”	DVL2	binding
FZD2	“up-regulates activity”	DVL2	binding
FZD5	“up-regulates activity”	DVL2	binding
DVL2	“up-regulates activity”	PLCB1
LRP1B	“down-regulates activity”	DVL2	binding
NHLRC1	“down-regulates quantity by destabilization”	DVL2	polyubiquitination
PTEN	“down-regulates activity”	DVL2	dephosphorylation
RIPK4	“up-regulates activity”	DVL2	phosphorylation
DVL2	“up-regulates activity”	LRP6	binding
RNF185	“down-regulates quantity by destabilization”	DVL2	polyubiquitination
CSNK1E	“up-regulates activity”	DVL2	phosphorylation
DVL2	“down-regulates activity”	RBPJ	binding
TM4SF1	“up-regulates activity”	DVL2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 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
Anchoring of the basal body to the plasma membrane	5	15.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	105
Likely benign	11
Benign	10

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
21017	NM_000018.4(ACADVL):c.1405C>T (p.Arg469Trp)	Likely pathogenic

SpliceAI

2278 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7226635:TAGGT:T	acceptor_gain	1.0000
17:7226638:GT:G	acceptor_gain	1.0000
17:7226640:C:CA	acceptor_loss	1.0000
17:7226640:C:CC	acceptor_gain	1.0000
17:7227085:CTTA:C	donor_loss	1.0000
17:7227086:TTAC:T	donor_loss	1.0000
17:7227087:TA:T	donor_loss	1.0000
17:7227088:A:AC	donor_gain	1.0000
17:7227088:AC:A	donor_loss	1.0000
17:7227088:ACAG:A	donor_gain	1.0000
17:7227089:C:CT	donor_gain	1.0000
17:7227089:CA:C	donor_gain	1.0000
17:7227089:CAG:C	donor_gain	1.0000
17:7227089:CAGC:C	donor_gain	1.0000
17:7227089:CAGCT:C	donor_gain	1.0000
17:7227235:C:CT	acceptor_gain	1.0000
17:7227269:CCTGG:C	acceptor_loss	1.0000
17:7227270:C:CA	acceptor_loss	1.0000
17:7227271:T:A	acceptor_loss	1.0000
17:7227281:C:CT	acceptor_gain	1.0000
17:7227281:C:T	acceptor_gain	1.0000
17:7227398:CCATA:C	donor_loss	1.0000
17:7227399:CATA:C	donor_loss	1.0000
17:7227400:ATAC:A	donor_loss	1.0000
17:7227401:TA:T	donor_loss	1.0000
17:7227402:A:AT	donor_loss	1.0000
17:7227402:AC:A	donor_gain	1.0000
17:7227403:C:CG	donor_loss	1.0000
17:7227403:CC:C	donor_gain	1.0000
17:7227454:T:TA	donor_gain	1.0000

AlphaMissense

4799 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7225880:A:C	F732L	1.000
17:7225880:A:T	F732L	1.000
17:7225882:A:G	F732L	1.000
17:7227126:A:C	Y503D	1.000
17:7227126:A:G	Y503H	1.000
17:7227129:A:C	Y502D	1.000
17:7227129:A:G	Y502H	1.000
17:7227130:G:C	C501W	1.000
17:7227131:C:T	C501Y	1.000
17:7227132:A:G	C501R	1.000
17:7227142:G:C	F497L	1.000
17:7227142:G:T	F497L	1.000
17:7227143:A:C	F497C	1.000
17:7227143:A:G	F497S	1.000
17:7227144:A:G	F497L	1.000
17:7227151:C:A	K494N	1.000
17:7227151:C:G	K494N	1.000
17:7227152:T:A	K494M	1.000
17:7227153:T:C	K494E	1.000
17:7227163:G:C	H490Q	1.000
17:7227163:G:T	H490Q	1.000
17:7227164:T:C	H490R	1.000
17:7227170:A:C	I488S	1.000
17:7227170:A:T	I488N	1.000
17:7227185:A:G	L483P	1.000
17:7227188:A:G	L482P	1.000
17:7227197:G:T	A479D	1.000
17:7227209:G:T	A475D	1.000
17:7227248:A:G	L462P	1.000
17:7227248:A:T	L462H	1.000

dbSNP variants (sampled 300 via entrez): RS1000274960 (17:7234478 C>T), RS1000598225 (17:7235015 G>A,C), RS1000676156 (17:7234567 C>T), RS1000821363 (17:7228831 C>T), RS1000852748 (17:7224909 A>C), RS1001217144 (17:7230216 G>A), RS1001279155 (17:7233610 A>T), RS1001774662 (17:7228782 A>G), RS1002226595 (17:7236423 G>A,T), RS1002666170 (17:7232565 C>T), RS1002763080 (17:7232420 A>G), RS1002925080 (17:7227584 G>A,C,T), RS1003211005 (17:7228358 G>A), RS1003226704 (17:7232717 A>G), RS1003252243 (17:7228558 T>C,G)

Disease associations

OMIM: gene MIM:602151 | disease phenotypes: MIM:201475

GenCC curated gene-disease

Disease	Classification	Inheritance
Robinow syndrome	Moderate	Autosomal dominant

Mondo (2): very long chain acyl-CoA dehydrogenase deficiency (MONDO:0008723), Robinow syndrome (MONDO:0019978)

Orphanet (1): Very long chain acyl-CoA dehydrogenase deficiency (Orphanet:26793)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009698_119	Metabolite levels	2.000000e-10
GCST009698_64	Metabolite levels	3.000000e-09
GCST009698_67	Metabolite levels	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005059	acylcarnitine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1255125 (SINGLE PROTEIN), CHEMBL3883307 (PROTEIN-PROTEIN INTERACTION)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2074216	DVL2		0.00	0

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.16	Ki	700	nM	CHEMBL1221418
5.92	Ki	1200	nM	CHEMBL1222068
5.34	Ki	4600	nM	CHEMBL1222069

PubChem BioAssay actives

3 with measured affinity, of 6 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoic acid	501059: Binding affinity at Dvl2 PDZ domain after 15 mins by fluorescence polarization assay	ki	0.7000	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]butanedioic acid	501059: Binding affinity at Dvl2 PDZ domain after 15 mins by fluorescence polarization assay	ki	1.2000	uM
(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylpentanoic acid	501059: Binding affinity at Dvl2 PDZ domain after 15 mins by fluorescence polarization assay	ki	4.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Niclosamide	decreases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
trichostatin A	affects cotreatment, affects expression	1
beta-lapachone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
3-deazaneplanocin	affects cotreatment, affects expression	1
ICG 001	increases expression	1
abrine	increases expression	1
PKF115-584	increases expression	1
jinfukang	increases expression	1
FV-429 compound	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Glyphosate	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atropine	decreases reaction, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Nicotine	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1227540	Binding	Binding affinity at Dvl2 PDZ domain after 15 mins by fluorescence polarization assay	Inhibition of Wnt signaling by Dishevelled PDZ peptides. — Nat Chem Biol

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1B5	SEES3-1V human DVL2, clone1	Embryonic stem cell	Male
CVCL_A1B6	SEES3-1V human DVL2, clone2	Embryonic stem cell	Male
CVCL_A1B7	SEES3-1V human DVL2, clone3	Embryonic stem cell	Male
CVCL_B9H5	Abcam A-549 DVL2 KO	Cancer cell line	Male
CVCL_D9DV	Ubigene HEK293 DVL2 KO	Transformed cell line	Female
CVCL_E0C8	Ubigene HeLa DVL2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00983788	PHASE2	COMPLETED	Effect of Bezafibrate on Muscle Metabolism in Patients With Fatty Acid Oxidation Defects
NCT01886378	PHASE2	COMPLETED	A Study of UX007 (Triheptanoin) in Participants With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)
NCT02214160	PHASE2	COMPLETED	Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies
NCT01494051	PHASE1/PHASE2	COMPLETED	High Protein Diet in Patients With Long-chain Fatty Acid Oxidation Disorders
NCT05411835	EARLY_PHASE1	COMPLETED	Oral Ketones and Exercise Among Patients With Long-chain Fatty Acid Oxidation Disorders
NCT02517307	Not specified	COMPLETED	Fatty Acid Oxidation Defects and Insulin Sensitivity
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT03531554	Not specified	COMPLETED	Acute Nutritional Ketosis in VLCAD Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan