DLL4

Summary

DLL4 (delta like canonical Notch ligand 4, HGNC:2910) is a protein-coding gene on chromosome 15q15.1, encoding Delta-like protein 4 (Q9NR61). Involved in the Notch signaling pathway as Notch ligand.

This gene is a homolog of the Drosophila delta gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain.

Source: NCBI Gene 54567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Adams-Oliver syndrome 6 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 342 total — 14 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_019074

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2910
Approved symbol	DLL4
Name	delta like canonical Notch ligand 4
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128917
Ensembl biotype	protein_coding
OMIM	605185
Entrez	54567

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000249749, ENST00000557876, ENST00000559440, ENST00000878560, ENST00000878561

RefSeq mRNA: 1 — MANE Select: NM_019074 NM_019074

CCDS: CCDS45232

Canonical transcript exons

ENST00000249749 — 11 exons

Exon	Start	End
ENSE00000338847	40929847	40930116
ENSE00000586209	40936228	40936930
ENSE00000675668	40934898	40935117
ENSE00000675693	40931503	40931766
ENSE00000675694	40930625	40930682
ENSE00001106361	40937418	40937526
ENSE00001539403	40938029	40939073
ENSE00002565031	40929340	40929734
ENSE00003499613	40932317	40932447
ENSE00003619549	40934548	40934717
ENSE00003629363	40932171	40932231

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 90.11.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7421 / max 192.4845, expressed in 657 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146152	3.7421	657

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	90.11	gold quality
apex of heart	UBERON:0002098	89.22	gold quality
body of tongue	UBERON:0011876	86.33	silver quality
pericardium	UBERON:0002407	86.05	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.20	gold quality
upper lobe of left lung	UBERON:0008952	85.14	gold quality
left ventricle myocardium	UBERON:0006566	85.12	gold quality
omental fat pad	UBERON:0010414	85.00	gold quality
peritoneum	UBERON:0002358	84.98	gold quality
nasal cavity epithelium	UBERON:0005384	84.87	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.62	gold quality
upper lobe of lung	UBERON:0008948	84.40	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.80	gold quality
cardiac muscle of right atrium	UBERON:0003379	83.42	gold quality
tongue	UBERON:0001723	83.07	silver quality
cardiac ventricle	UBERON:0002082	83.02	gold quality
heart left ventricle	UBERON:0002084	83.02	gold quality
upper arm skin	UBERON:0004263	82.88	gold quality
vastus lateralis	UBERON:0001379	81.99	gold quality
cardiac atrium	UBERON:0002081	81.99	gold quality
cardia of stomach	UBERON:0001162	81.87	silver quality
right atrium auricular region	UBERON:0006631	81.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	81.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.52	gold quality
saphenous vein	UBERON:0007318	81.48	silver quality
subthalamic nucleus	UBERON:0001906	81.28	silver quality
pons	UBERON:0000988	81.15	silver quality
epithelial cell of pancreas	CL:0000083	81.07	gold quality
body of uterus	UBERON:0009853	81.03	gold quality
left lobe of thyroid gland	UBERON:0001120	81.00	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	737.09
E-GEOD-135922	yes	452.06
E-ANND-3	yes	8.92
E-MTAB-5061	yes	6.17
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
CASP3	Activation
CASP8	Activation
FLT1	Activation
HES1	Activation
KDR	Repression
MAPK1	Repression
MAPK3	Repression
NOTCH4	Activation
NRP1	Repression
TNF	Activation
TNFSF10	Activation

Upstream regulators (CollecTRI, top): ASCL1, FOXC1, FOXC2, FOXN1, FOXN4, HIF1A, NFE2L2, NOTCH1, NOTCH4, PDCD10, RBPJ, SIRT1, SOX18, SOX7, VEGFA

miRNA regulators (miRDB)

90 targeting DLL4, 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-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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 40)

• Ectopic expression of human Delta4 in mice by retroviral gene delivery impairs hematopoietic development and leads to lymphoproliferative disease. (PMID:12200365)
• We show here that vascular endothelial growth factor but not basic fibroblast growth factor can induce gene expression of Notch1 and Dll4, in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 (PMID:12482957)
• suppresses the self-renewal capacity and long-term growth of two myeloblastic leukemia cell lines (PMID:12684674)
• upon transduction into cord blood CD34+ stem cells, DLL4 induced a 25-fold reduction in nucleated cell production by maintaining a higher proportion of cells in G0/G1 phase; specific retention of CD34+ cells throughout the culture was observed. (PMID:14990974)
• DLL4 not associated with susceptibility to periodic catatonia in German patients from 15q15 linked families (PMID:15820317)
• DLL4 expression is essential for tumor angiogenesis. (PMID:16204037)
• DLL4 expression is associated with vascular differentiation in bladder cancer. (PMID:16914569)
• CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement. (PMID:17157169)
• Dll4-triggered Notch signaling may mediate inflammatory responses in macrophages and promote inflammation. (PMID:17533181)
• Notch1 ligand, Delta-like ligand-4, stimulates R-Ras-dependent alpha 5 beta 1 integrin-mediated adhesion, demonstrating the physiological relevance of this pathway. (PMID:17664272)
• Dll4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. (PMID:17692341)
• Overexpression of DLL4 is associated with breast cancer (PMID:17822320)
• Endometrial Dll4 may enhance the development of the endometrial microvascular system and facilitate the implantation of blastocyst in a fertile cycle. (PMID:17916635)
• integrated role of dll4 with interleukin-12 demonstrated that, together, both of these instructive signals direct the immune response toward a more competent, less pathogenic antiviral response. (PMID:17998388)
• The effects of a soluble form of Delta4 (solD4) by exposing CD34+CD38(low) cells to S17 feeders engineered to express solD4 (solD4/S17), were assessed. (PMID:18055448)
• Overexpression of Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth (PMID:18056450)
• Dll4 may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways. (PMID:18339870)
• Global intrinsic (conformational) disorder, in concert with local preorganization, may play a role in Notch signaling mediated by Delta-4. (PMID:18435556)
• retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor-induced endothelial cell growth (PMID:18577711)
• Escape of human T-cell acute lymphoblastic leukemia cells from dormancy is associated with increased Notch3 signaling in tumor cells (PMID:19208840)
• dynamic changes in neurite morphology were rapidly reversible and dependent on the activation of the Notch signaling pathway (PMID:19263417)
• possible complementary role for JAG1 and DLL4 in the context of Kaposi sarcoma. (PMID:19816565)
• Studies indicate that the imbalance of pro-angiogenic and anti-angiogenic factors VEGFA, Notch, Dll4, PDGF and angiopoietin-1 promotes tumor angiogenesis. (PMID:20036815)
• This review focuses on negative regulators of angiogenesis delta-like 4 and vasohibin 1 produced by endothelial cells. (PMID:20167561)
• vascular notch ligand delta-like 4 is expressed with inflammatory markers in breast cancer (PMID:20167860)
• Results suggests that cell-to-cell interaction via DLL4-Notch signaling pathway has been implicated in tumor angiogenesis, and control of this pathway can be a new therapeutic approach to solid tumor. (PMID:20182391)
• Inhibiting the Dll4/Notch signal transduction pathway stimulates the proliferation of HUVEC and facilitates angiogenesis. (PMID:20193271)
• Dll4/Notch interaction is essential for proper reparative angiogenesis. Moreover, Dll4/Notch signaling regulates sprouting angiogenesis and coordinates the interaction between inflammation and angiogenesis under ischemic conditions. (PMID:20508179)
• exosomes can transfer the Dll4 protein to other endothelial cells and incorporate it into their cell membrane, which results in an inhibition of Notch signaling and a loss of Notch receptor (PMID:20558614)
• DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs. (PMID:20959466)
• Studies indicate that different receptors and ligands expression in breast cancer and various ways in which the pathway can be inhibited. (PMID:21045140)
• the Ang1/Tie2 signal potentiates basal Notch signal controlling vascular quiescence by up-regulating Dll4 through AKT-mediated activation of beta-catenin. (PMID:21212269)
• DLL4 signaling appears to play an essential role in the biological behavior of choroid vascular endothelial cells under hypoxia. (PMID:21362319)
• Through activating the Dll4-Notch-Hey2 signaling pathway, HGF indirectly promotes the proliferation and migration ability of cells, so that offspring artery branches are formed. (PMID:21362320)
• we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1 (PMID:21372153)
• SiRNA-mediated knockdown of alpha2beta1 and alpha6beta1 integrins abolishes Dll4 induction, which discloses a selective integrin signaling acting upstream of Notch pathway (PMID:21474814)
• Expression of DLL4, VEGF and HIF-1alpha was very strong in gliomas. (PMID:21517260)
• Dll4 play an important role in choroidal neovascularization (CNV) angiogenesis, which appears to be regulated by HIF-1alpha and VEGF during the progression of CNV under hypoxic conditions. (PMID:21526177)
• The receptors Notch2, -3, -4 and their ligands Jagged1, -2 and Delta1, -4 were detected at both the mRNA and protein level in early and late placenta (PMID:21726900)
• we show that Tis11b silencing in endothelial cells leads to up-regulation of Dll4 protein and mRNA expressions, indicating that Dll4 is a physiological target of Tis11b (PMID:21832157)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dll4	ENSMUSG00000027314
rattus_norvegicus	Dll4	ENSRNOG00000014011
drosophila_melanogaster	Ser	FBGN0004197
caenorhabditis_elegans	paml-2	WBGENE00009114
caenorhabditis_elegans		WBGENE00013498

Paralogs (5): JAG1 (ENSG00000101384), JAG2 (ENSG00000184916), DNER (ENSG00000187957), DLL1 (ENSG00000198719), NOTCH4 (ENSG00000204301)

Protein

Protein identifiers

Delta-like protein 4 — Q9NR61 (reviewed: Q9NR61)

Alternative names: Drosophila Delta homolog 4

All UniProt accessions (1): Q9NR61

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the Notch signaling pathway as Notch ligand. Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types. During spinal cord neurogenesis, inhibits V2a interneuron fate.

Subunit / interactions. Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).

Subcellular location. Cell membrane.

Tissue specificity. Expressed in vascular endothelium.

Disease relevance. Adams-Oliver syndrome 6 (AOS6) [MIM:616589] A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor.

RefSeq proteins (1): NP_061947* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001774	DSL	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011651	Notch_ligand_N	Domain
IPR051022

Pfam: PF00008, PF01414, PF07657, PF21700

UniProt features (87 total): disulfide bond 29, strand 23, domain 9, sequence variant 7, glycosylation site 4, turn 4, region of interest 2, site 2, topological domain 2, helix 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5MVX	X-RAY DIFFRACTION	2.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR61-F1	74.89	0.36

Functional residue map

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

Catalytic / active sites (2): 110 (interaction with notch1); 216 (interaction with notch1)

Disulfide bonds (29): 50–54, 61–74, 175–184, 188–200, 208–217, 222–233, 226–239, 241–250, 253–264, 259–270, 272–281, 288–300, 294–310, 312–321, 328–339, 333–348, 350–359, 366–377, 371–388, 390–399 …

Glycosylation sites (4): 108, 183, 205, 393

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2660826	Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus

MSigDB gene sets: 482 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, AHRARNT_01, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_SIGNALING_BY_NOTCH, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, PAX4_01, GOBP_HEART_TRABECULA_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497

GO Biological Process (36): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), branching involved in blood vessel morphogenesis (GO:0001569), blood vessel remodeling (GO:0001974), aortic valve morphogenesis (GO:0003180), cardiac ventricle morphogenesis (GO:0003208), cardiac atrium morphogenesis (GO:0003209), ventricular trabecula myocardium morphogenesis (GO:0003222), pericardium morphogenesis (GO:0003344), signal transduction (GO:0007165), Notch signaling pathway (GO:0007219), visual perception (GO:0007601), negative regulation of cell population proliferation (GO:0008285), negative regulation of endothelial cell migration (GO:0010596), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), T cell differentiation (GO:0030217), dorsal aorta morphogenesis (GO:0035912), cellular response to vascular endothelial growth factor stimulus (GO:0035924), cellular response to fibroblast growth factor stimulus (GO:0044344), negative regulation of Notch signaling pathway (GO:0045746), positive regulation of Notch signaling pathway (GO:0045747), regulation of neurogenesis (GO:0050767), ventral spinal cord interneuron fate commitment (GO:0060579), regulation of neural retina development (GO:0061074), blood vessel lumenization (GO:0072554), negative regulation of cell migration involved in sprouting angiogenesis (GO:0090051), negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903588), positive regulation of neural precursor cell proliferation (GO:2000179), cell communication (GO:0007154), multicellular organism development (GO:0007275), nervous system development (GO:0007399), cell differentiation (GO:0030154), negative regulation of blood vessel endothelial cell migration (GO:0043537), animal organ development (GO:0048513), system development (GO:0048731)

GO Molecular Function (4): Notch binding (GO:0005112), calcium ion binding (GO:0005509), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	2
cardiac chamber morphogenesis	2
gene expression	2
regulation of gene expression	2
cellular response to growth factor stimulus	2
signaling receptor binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
anatomical structure formation involved in morphogenesis	1
angiogenesis	1
branching morphogenesis of an epithelial tube	1
tissue remodeling	1
aortic valve development	1
heart valve morphogenesis	1
cardiac ventricle development	1
cardiac atrium development	1
ventricular cardiac muscle tissue morphogenesis	1
heart trabecula morphogenesis	1
morphogenesis of an epithelial sheet	1
embryonic morphogenesis	1
pericardium development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
sensory perception of light stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of endothelial cell migration	1
negative regulation of cell migration	1
endothelial cell migration	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
lymphocyte differentiation	1
T cell activation	1
dorsal aorta development	1

Protein interactions and networks

STRING

2742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLL4	NOTCH2	Q04721	991
DLL4	NOTCH1	P46531	988
DLL4	NOTCH4	Q99466	988
DLL4	NOTCH3	Q9UM47	987
DLL4	RBPJ	Q06330	872
DLL4	EFNB2	P52799	820
DLL4	FLT4	P35916	803
DLL4	HEY1	Q9Y5J3	792
DLL4	KDR	P35968	787
DLL4	FLT1	P16057	761
DLL4	HEY2	Q9UBP5	748
DLL4	MAML1	Q92585	701
DLL4	NRARP	Q7Z6K4	698
DLL4	NR2F2	P24468	694
DLL4	CTNNB1	P35222	691

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SYNJ2BP	DLL4	psi-mi:“MI:0915”(physical association)	0.560
SYNJ2BP	DLL4	psi-mi:“MI:0403”(colocalization)	0.560
DLL4	NOTCH1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (2): DLL4 (Positive Genetic), DLL4 (Co-fractionation)

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A0A1F4, A2RUV0, A4FV93, A8X481, B2LW77, B8JI71, D3ZHH1, D3ZUK3, G5EFX6, O00548, O35161, O35474, O43854, O57409, O88278, P07898, P10040, P10041, P18168, P21783, P78504, P82279, P97607, P97677, Q14517, Q19319, Q20911, Q28670, Q2PZL6, Q5IJ48, Q5R7K9, Q5ZQU0, Q61483, Q63722, Q6DI48, Q6UY11, Q6V0I7, Q70E20, Q80YA8, Q8JZM4

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
DLL4	“up-regulates activity”	NOTCH1	binding
DLL4	“down-regulates quantity by repression”	KDR	“transcriptional regulation”
DLL4	“down-regulates quantity by repression”	NRP1	“transcriptional regulation”
VEGFA	“up-regulates quantity by expression”	DLL4	“transcriptional regulation”
MIB1	“up-regulates activity”	DLL4	ubiquitination
DLL4	“up-regulates activity”	PP2B	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	13
Uncertain significance	146
Likely benign	115
Benign	21

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
204368	NM_019074.4(DLL4):c.1660C>T (p.Gln554Ter)	Pathogenic
204369	NM_019074.4(DLL4):c.1672C>T (p.Arg558Ter)	Pathogenic
204370	NM_019074.4(DLL4):c.1365C>G (p.Cys455Trp)	Pathogenic
204372	NM_019074.4(DLL4):c.1168T>C (p.Cys390Arg)	Pathogenic
204373	NM_019074.4(DLL4):c.556C>T (p.Arg186Cys)	Pathogenic
204375	NM_019074.4(DLL4):c.361G>C (p.Ala121Pro)	Pathogenic
204376	NM_019074.4(DLL4):c.583T>C (p.Phe195Leu)	Pathogenic
2082857	NM_019074.4(DLL4):c.1240G>A (p.Gly414Arg)	Pathogenic
2101441	NM_019074.4(DLL4):c.353del (p.Ile118fs)	Pathogenic
3652389	NM_019074.4(DLL4):c.1528del (p.Tyr510fs)	Pathogenic
523582	NM_019074.4(DLL4):c.1825C>T (p.Gln609Ter)	Pathogenic
523591	NM_019074.4(DLL4):c.1310G>C (p.Cys437Ser)	Pathogenic
523592	NM_019074.4(DLL4):c.1397G>A (p.Cys466Tyr)	Pathogenic
929444	NM_019074.4(DLL4):c.1857_1864del (p.Pro621fs)	Pathogenic
1320129	NM_019074.4(DLL4):c.784G>A (p.Gly262Ser)	Likely pathogenic
2506498	NM_019074.4(DLL4):c.1396T>C (p.Cys466Arg)	Likely pathogenic
2630670	NM_019074.4(DLL4):c.572G>A (p.Arg191His)	Likely pathogenic
3066222	NM_019074.4(DLL4):c.187A>G (p.Lys63Glu)	Likely pathogenic
3252693	NM_019074.4(DLL4):c.1944-1G>C	Likely pathogenic
3254751	NM_019074.4(DLL4):c.329C>T (p.Thr110Ile)	Likely pathogenic
3346228	NM_019074.4(DLL4):c.1998C>G (p.Tyr666Ter)	Likely pathogenic
3600511	NM_019074.4(DLL4):c.1424G>C (p.Cys475Ser)	Likely pathogenic
4526789	NM_019074.4:c.1102_1835del	Likely pathogenic
520578	NM_019074.4(DLL4):c.1679_1689del (p.Pro560fs)	Likely pathogenic
523590	NM_019074.4(DLL4):c.949A>C (p.Thr317Pro)	Likely pathogenic
800940	NM_019074.4(DLL4):c.1392C>A (p.Cys464Ter)	Likely pathogenic
992895	NM_019074.4(DLL4):c.82G>C (p.Gly28Arg)	Likely pathogenic

SpliceAI

1658 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40929730:AGCAG:A	donor_loss	1.0000
15:40929732:CAG:C	donor_loss	1.0000
15:40929733:AG:A	donor_loss	1.0000
15:40929734:GG:G	donor_loss	1.0000
15:40929735:GTAAC:G	donor_loss	1.0000
15:40929736:T:A	donor_loss	1.0000
15:40930679:CCAGG:C	donor_loss	1.0000
15:40930681:AGGT:A	donor_loss	1.0000
15:40930682:GGTG:G	donor_loss	1.0000
15:40930683:G:C	donor_loss	1.0000
15:40930684:T:G	donor_loss	1.0000
15:40931695:GCCAC:G	donor_gain	1.0000
15:40931762:ACAGC:A	donor_gain	1.0000
15:40931765:GC:G	donor_gain	1.0000
15:40931767:G:GG	donor_gain	1.0000
15:40932232:G:GG	donor_gain	1.0000
15:40932315:A:AG	acceptor_gain	1.0000
15:40932316:G:GG	acceptor_gain	1.0000
15:40932316:GC:G	acceptor_gain	1.0000
15:40932316:GCT:G	acceptor_gain	1.0000
15:40932445:AAGG:A	donor_loss	1.0000
15:40932448:G:T	donor_loss	1.0000
15:40932449:T:A	donor_loss	1.0000
15:40934544:GCAG:G	acceptor_loss	1.0000
15:40934545:CAGA:C	acceptor_loss	1.0000
15:40934546:A:AG	acceptor_gain	1.0000
15:40934546:A:AT	acceptor_loss	1.0000
15:40934547:G:GT	acceptor_gain	1.0000
15:40934547:GAT:G	acceptor_gain	1.0000
15:40934710:GCT:G	donor_gain	1.0000

AlphaMissense

4495 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:40931744:G:C	W212C	1.000
15:40931744:G:T	W212C	1.000
15:40932332:G:C	W245C	1.000
15:40932332:G:T	W245C	1.000
15:40932425:G:C	W276C	1.000
15:40932425:G:T	W276C	1.000
15:40932345:T:A	C250S	0.999
15:40932346:G:C	C250S	0.999
15:40932405:T:A	C270S	0.999
15:40932406:G:C	C270S	0.999
15:40932438:T:A	C281S	0.999
15:40932438:T:C	C281R	0.999
15:40932439:G:A	C281Y	0.999
15:40932439:G:C	C281S	0.999
15:40932439:G:T	C281F	0.999
15:40932440:T:G	C281W	0.999
15:40935072:T:A	C399S	0.999
15:40935073:G:C	C399S	0.999
15:40930113:G:C	W111C	0.998
15:40930113:G:T	W111C	0.998
15:40932354:T:A	C253S	0.998
15:40932355:G:C	C253S	0.998
15:40932372:T:A	C259S	0.998
15:40932373:G:C	C259S	0.998
15:40932429:G:T	G278C	0.998
15:40934559:T:A	C288S	0.998
15:40934560:G:C	C288S	0.998
15:40934658:T:A	C321S	0.998
15:40934659:G:A	C321Y	0.998
15:40934659:G:C	C321S	0.998

dbSNP variants (sampled 300 via entrez): RS1000000367 (15:40938359 T>C,G), RS1000093522 (15:40938140 G>A), RS1000619290 (15:40930460 C>G,T), RS1000685991 (15:40928429 G>A), RS1000962485 (15:40939363 C>A), RS1001563578 (15:40935469 G>A,T), RS1001828209 (15:40937048 G>T), RS1001845038 (15:40930740 A>T), RS1002504603 (15:40933404 C>T), RS1002652179 (15:40928188 TGG>T), RS1002658065 (15:40936478 C>T), RS1002663448 (15:40928437 A>G), RS1002688817 (15:40930861 A>C,G,T), RS1003494693 (15:40938330 C>T), RS1003558729 (15:40938043 C>A,G,T)

Disease associations

OMIM: gene MIM:605185 | disease phenotypes: MIM:616589, MIM:100300, MIM:616220

GenCC curated gene-disease

Disease	Classification	Inheritance
Adams-Oliver syndrome 6	Definitive	Autosomal dominant
aplasia cutis congenita	Supportive	Autosomal dominant
Adams-Oliver syndrome	Supportive	Autosomal dominant

Mondo (4): Adams-Oliver syndrome 6 (MONDO:0014703), Adams-Oliver syndrome (MONDO:0007034), focal segmental glomerulosclerosis 9 (MONDO:0014539), aplasia cutis congenita (MONDO:0007145)

Orphanet (2): Adams-Oliver syndrome (Orphanet:974), Hereditary steroid-resistant nephrotic syndrome (Orphanet:656)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000089	Renal hypoplasia
HP:0000238	Hydrocephalus
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000965	Cutis marmorata
HP:0001057	Aplasia cutis congenita
HP:0001156	Brachydactyly
HP:0001159	Syndactyly
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001269	Hemiparesis
HP:0001276	Hypertonia
HP:0001362	Calvarial skull defect
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001409	Portal hypertension
HP:0001508	Failure to thrive
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001622	Premature birth
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001641	Abnormal pulmonary valve morphology
HP:0001660	Truncus arteriosus
HP:0001744	Splenomegaly
HP:0001770	Toe syndactyly
HP:0001800	Hypoplastic toenails

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001524_12	Visceral adipose tissue/subcutaneous adipose tissue ratio	3.000000e-06
GCST005316_541	Intelligence (MTAG)	9.000000e-11
GCST006269_762	General cognitive ability	5.000000e-09
GCST009391_495	Metabolite levels	4.000000e-06
GCST009597_252	Multiple sclerosis	3.000000e-06
GCST010002_167	Refractive error	3.000000e-11
GCST010725_23	Malaria	2.000000e-06
GCST010725_38	Malaria	3.000000e-06
GCST010725_80	Malaria	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004337	intelligence
EFO:0005001	phenylalanine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538225	Adams Oliver syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712916 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	increases expression	1
TL8-506	affects cotreatment, increases expression	1
bufotalin	increases expression	1
oxybenzone	decreases expression	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cypermethrin	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
stearic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression, decreases reaction	1
epigallocatechin gallate	affects cotreatment, increases expression	1
2-ethyl-5-carboxypentyl phthalate	increases abundance, increases expression	1
deguelin	decreases expression	1
pyrimidifen	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
licochalcone B	increases expression	1
bisphenol S	increases expression	1
picoxystrobin	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1

Cellosaurus cell lines

4 cell lines: 1 transformed cell line, 1 induced pluripotent stem cell, 1 embryonic stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9DH	Ubigene HEK293 DLL4 KO	Transformed cell line	Female
CVCL_DQ81	GENYOi001-A-2	Induced pluripotent stem cell	Female
CVCL_DQ83	WAe009-A-6	Embryonic stem cell	Female
CVCL_E6Q6	Genomeditech CHO-K1 H_DLL4	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01678105	PHASE2	COMPLETED	A Phase II Study of Dovitinib in Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Salivary Glands
NCT06066333	PHASE2	RECRUITING	Study of Radiotherapy and Pembrolizumab in People With Adrenocortical Carcinoma
NCT01898715	PHASE1	COMPLETED	Phase 1 Study of ATR-101 in Subjects With Advanced Adrenocortical Carcinoma
NCT01262235	PHASE1/PHASE2	COMPLETED	A Dose Finding Study of TKM-080301 Infusion in Neuroendocrine Tumors (NET) and Adrenocortical Carcinoma (ACC) Patients
NCT00170326	Not specified	COMPLETED	Progressive Ventricular Dysfunction Prevention in Pacemaker Patients
NCT01117792	Not specified	COMPLETED	Subcutaneous Implantable Defibrillator (S-ICD) System - CE Clinical Investigation
NCT01630421	Not specified	RECRUITING	Genetic and Functional Analysis of Aplasia Cutis Congenital (ACC)