DLL4 delta like canonical Notch ligand 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: DLL4provided by HGNC
Official Full Name: delta like canonical Notch ligand 4provided by HGNC
Primary source: HGNC:HGNC:2910
See related: Ensembl:ENSG00000128917 MIM:605185
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: AOS6; delta4; hdelta2
Summary: 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. [provided by RefSeq, Jul 2008]
Expression: Broad expression in placenta (RPKM 11.5), fat (RPKM 11.2) and 22 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 15q15.1

Exon count:: 11

Annotation release	Status	Assembly	Chr	Location
109.20191205	current	GRCh38.p13 (GCF_000001405.39)	15	NC_000015.10 (40929340..40939073)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	15	NC_000015.9 (41221531..41231258)

Chromosome 15 - NC_000015.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

data demonstrates a surface-based method to spatially pattern Dll4 to gain control over endothelial sprout location and direction
Title: Spatial patterning of the Notch ligand Dll4 controls endothelial sprouting in vitro.
The results demonstrate that ephrin-B2 and Dll4 mediated co-dependence of hepatocellular carcinoma and endothelial progenitor cells intercellular crosstalk in the initial stages of hepatocellular carcinoma establishment and development.
Title: Tumor-endothelial cell interaction in an experimental model of human hepatocellular carcinoma.
TR3/Nur77 regulated the expression of DLL4 and Jagged1 in culture endothelial cells. DLL4 and Jagged1 play important roles in the angiogenic responses induced by TR3/Nur77.
Title: DLL4 and Jagged1 are angiogenic targets of orphan nuclear receptor TR3/Nur77.
Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of Diabetic foot ulcerations.
Title: Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes.
These data indicate that DLL4 represents a new prognostic biomarker for nonsmall cell lung cancer , and DLL4 overexpression inhibits cell proliferation and metastasis in vitro.
Title: Downregulation of DLL4 predicts poor survival in non‑small cell lung cancer patients due to promotion of lymph node metastasis.
Study demonstrates that DLL4 is important in regulating the tumour growth of hepatitis B virus (HBV)-associated hepatocellular carcinoma as well as the neovascularization and suppression of HBV replication.
Title: Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication.
this study revealed that DLL4 has pathophysiological roles on the progression of esophagus cancer cells, including migration, invasion and apoptosis, which indicated that DLL4 may be considered as a potent therapeutic target for the treatment of malignant esophageal cancer.
Title: Stable silencing of dll4 gene suppresses the growth and metastasis of esophagus cancer cells by attenuating Akt phosphorylation.
The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.
Title: LDB2 regulates the expression of DLL4 through the formation of oligomeric complexes in endothelial cells.
Data show that Delta-like 4 (DLL4) and Jagged1 (JAG1) displayed equal potency in stimulating Notch target genes in HMEC-1 dermal microvascular endothelial cells but had opposing effects on sprouting angiogenesis in vitro.
Title: Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth.
epigenetic silencing and TP53 mutation have an effect on the expression of DLL4 in human cancer stem disorder
Title: The effect of epigenetic silencing and TP53 mutation on the expression of DLL4 in human cancer stem disorder.

Submit: New GeneRIF Correction See all GeneRIFs (114)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Adams-Oliver syndrome 6 MedGen: C4225271 OMIM: 616589 GeneReviews: Not available	Compare labs

NHGRI GWAS Catalog

Description
Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

NoName (e-PCR)
- UniSTS:70152

UniSTS:465451 (e-PCR)
- UniSTS:465451

Dll4 (e-PCR), detects polymorphism
- UniSTS:465451

PMC316657P1 (e-PCR)
- UniSTS:273027

PMC316657P2 (e-PCR)
- UniSTS:273028

DLL4_593 (e-PCR)
- UniSTS:277166

RH78211 (e-PCR)
- UniSTS:84154

Homology

Homologs of the DLL4 gene: The DLL4 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 287 organisms have orthologs with human gene DLL4
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
Notch binding	IBA Inferred from Biological aspect of Ancestor more info	PubMed
calcium ion binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
Notch signaling involved in heart development	ISS Inferred from Sequence or Structural Similarity more info
Notch signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
Notch signaling pathway	TAS Traceable Author Statement more info
T cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
angiogenesis	ISS Inferred from Sequence or Structural Similarity more info
aortic valve morphogenesis	IC Inferred by Curator more info	PubMed
blood circulation	TAS Traceable Author Statement more info	PubMed
blood vessel lumenization	IEA Inferred from Electronic Annotation more info
blood vessel remodeling	ISS Inferred from Sequence or Structural Similarity more info
branching involved in blood vessel morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
cardiac atrium morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
cardiac ventricle morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
cellular response to fibroblast growth factor stimulus	IDA Inferred from Direct Assay more info	PubMed
cellular response to vascular endothelial growth factor stimulus	IMP Inferred from Mutant Phenotype more info	PubMed
dorsal aorta morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of Notch signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
negative regulation of Notch signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	IDA Inferred from Direct Assay more info	PubMed
negative regulation of cell migration involved in sprouting angiogenesis	IDA Inferred from Direct Assay more info	PubMed
negative regulation of cell migration involved in sprouting angiogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of endothelial cell migration	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of gene expression	IDA Inferred from Direct Assay more info	PubMed
negative regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info
pericardium morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of Notch signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of gene expression	IDA Inferred from Direct Assay more info	PubMed
positive regulation of neural precursor cell proliferation	ISS Inferred from Sequence or Structural Similarity more info
regulation of neural retina development	ISS Inferred from Sequence or Structural Similarity more info
regulation of neurogenesis	IEA Inferred from Electronic Annotation more info
signal transduction	TAS Traceable Author Statement more info	PubMed
ventral spinal cord interneuron fate commitment	IMP Inferred from Mutant Phenotype more info	PubMed
ventricular trabecula myocardium morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
visual perception	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
integral component of membrane	IEA Inferred from Electronic Annotation more info
plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: delta-like protein 4

Names: delta 4; delta ligand 4; delta-like 4 homolog; delta-like 4 protein; drosophila Delta homolog 4; notch ligand DLL4; notch ligand delta-2

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_046974.1 RefSeqGene

Range

5008..14741

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_019074.4 → NP_061947.1 delta-like protein 4 precursor

See identical proteins and their annotated locations for NP_061947.1

Status: REVIEWED

Source sequence(s)

AB036931, AI478830, BC106950, DA089757, HY291308

Consensus CDS

CCDS45232.1

UniProtKB/Swiss-Prot

Q9NR61

Related

ENSP00000249749.5, ENST00000249749.7

Conserved Domains (3) summary

cd00054
Location:327 → 360

EGF_CA; Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the ...

pfam01414
Location:155 → 217

DSL; Delta serrate ligand

pfam07657
Location:27 → 88

MNNL; N terminus of Notch ligand