DLL4 (delta like canonical Notch ligand 4)

Gene

• Entrez ID: 54567
• Gene name: Delta like canonical Notch ligand 4
• Gene symbol: DLL4
• Synonyms (NCBI Gene): AOS6, delta4, hdelta2
• Chromosome: 15
• Chromosome location: 15q15.1
• 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]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs61750844	C>T	Pathogenic	Stop gained, coding sequence variant
rs796065344	C>T	Pathogenic	Coding sequence variant, stop gained
rs796065345	C>G,T	Pathogenic	Synonymous variant, coding sequence variant, missense variant
rs796065346	G>A	Pathogenic	Coding sequence variant, missense variant
rs796065347	T>C	Pathogenic	Coding sequence variant, missense variant
rs796065348	C>T	Pathogenic	Coding sequence variant, missense variant
rs796065349	C>A,T	Pathogenic, uncertain-significance	Coding sequence variant, missense variant
rs796065350	G>C	Pathogenic	Coding sequence variant, missense variant
rs796065351	T>C	Pathogenic	Coding sequence variant, missense variant
rs1247027543	G>A	Pathogenic	Coding sequence variant, missense variant
rs1555393027	A>C	Likely-pathogenic	Missense variant, coding sequence variant
rs1555393125	G>C	Pathogenic	Missense variant, coding sequence variant
rs1555393172	CGGACGACGGC>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1555393182	C>T	Pathogenic	Stop gained, coding sequence variant
rs1596194950	C>A	Likely-pathogenic	Coding sequence variant, stop gained

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT054328	hsa-miR-30b-5p	In situ hybridization, Luciferase reporter assay, qRT-PCR, Western blot	23086751
MIRT054329	hsa-miR-30c-5p	In situ hybridization, Luciferase reporter assay, qRT-PCR, Western blot	23086751
MIRT491290	hsa-miR-3943	PAR-CLIP	23592263
MIRT491289	hsa-miR-345-3p	PAR-CLIP	23592263
MIRT491288	hsa-miR-1203	PAR-CLIP	23592263
MIRT491287	hsa-miR-6125	PAR-CLIP	23592263
MIRT491286	hsa-miR-1225-3p	PAR-CLIP	23592263
MIRT491285	hsa-miR-4313	PAR-CLIP	23592263
MIRT491284	hsa-miR-4533	PAR-CLIP	23592263
MIRT491283	hsa-miR-4743-5p	PAR-CLIP	23592263
MIRT733755	hsa-miR-182-5p	Luciferase reporter assay, qRT-PCR, Western blotting	31996265
MIRT733755	hsa-miR-182-5p	Luciferase reporter assay, qRT-PCR, Western blotting	31996265
MIRT733755	hsa-miR-182-5p	Luciferase reporter assay, Western blotting, Immunoprecipitaion (IP), Immunofluorescence, qRT-PCR, Flow cytometry	31996265
MIRT054329	hsa-miR-30c-5p	Luciferase reporter assay, Western blotting, qRT-PCR, In situ hybridization, ELISA	33861889
MIRT054329	hsa-miR-30c-5p	Luciferase reporter assay, Western blotting, Immunohistochemistry (IHC), Immunofluorescence, qRT-PCR, In situ hybridization, ELISA	33861889
MIRT491290	hsa-miR-3943	PAR-CLIP	23592263
MIRT491289	hsa-miR-345-3p	PAR-CLIP	23592263
MIRT491288	hsa-miR-1203	PAR-CLIP	23592263
MIRT491287	hsa-miR-6125	PAR-CLIP	23592263
MIRT491286	hsa-miR-1225-3p	PAR-CLIP	23592263
MIRT491285	hsa-miR-4313	PAR-CLIP	23592263
MIRT491284	hsa-miR-4533	PAR-CLIP	23592263
MIRT491283	hsa-miR-4743-5p	PAR-CLIP	23592263
MIRT938768	hsa-miR-1252	CLIP-seq
MIRT938769	hsa-miR-298	CLIP-seq
MIRT938770	hsa-miR-30a	CLIP-seq
MIRT938771	hsa-miR-30b	CLIP-seq
MIRT938772	hsa-miR-30c	CLIP-seq
MIRT938773	hsa-miR-30d	CLIP-seq
MIRT938774	hsa-miR-30e	CLIP-seq
MIRT938775	hsa-miR-4476	CLIP-seq
MIRT938776	hsa-miR-4495	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
SIRT1	Repression	20631301

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IEA
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	ISS
GO:0001525	Process	Angiogenesis	IEA
GO:0001525	Process	Angiogenesis	IEA
GO:0001525	Process	Angiogenesis	ISS
GO:0001569	Process	Branching involved in blood vessel morphogenesis	IEA
GO:0001569	Process	Branching involved in blood vessel morphogenesis	ISS
GO:0001974	Process	Blood vessel remodeling	IEA
GO:0001974	Process	Blood vessel remodeling	ISS
GO:0003180	Process	Aortic valve morphogenesis	IDA	26491108
GO:0003208	Process	Cardiac ventricle morphogenesis	IEA
GO:0003208	Process	Cardiac ventricle morphogenesis	ISS
GO:0003209	Process	Cardiac atrium morphogenesis	IEA
GO:0003209	Process	Cardiac atrium morphogenesis	ISS
GO:0003222	Process	Ventricular trabecula myocardium morphogenesis	IEA
GO:0003222	Process	Ventricular trabecula myocardium morphogenesis	ISS
GO:0003344	Process	Pericardium morphogenesis	IEA
GO:0003344	Process	Pericardium morphogenesis	ISS
GO:0005112	Function	Notch binding	IBA
GO:0005112	Function	Notch binding	IEA
GO:0005112	Function	Notch binding	IPI	23839946
GO:0005112	Function	Notch binding	TAS	10837024
GO:0005509	Function	Calcium ion binding	IEA
GO:0005515	Function	Protein binding	IPI	24025447
GO:0005886	Component	Plasma membrane	IBA
GO:0005886	Component	Plasma membrane	IEA
GO:0005886	Component	Plasma membrane	TAS
GO:0007154	Process	Cell communication	IEA
GO:0007165	Process	Signal transduction	TAS	10837024
GO:0007219	Process	Notch signaling pathway	IBA
GO:0007219	Process	Notch signaling pathway	IDA	23839946
GO:0007219	Process	Notch signaling pathway	IEA
GO:0007219	Process	Notch signaling pathway	IEA
GO:0007219	Process	Notch signaling pathway	ISS
GO:0007399	Process	Nervous system development	IEA
GO:0007601	Process	Visual perception	IEA
GO:0008285	Process	Negative regulation of cell population proliferation	IMP	20616313
GO:0010596	Process	Negative regulation of endothelial cell migration	IMP	20616313
GO:0010628	Process	Positive regulation of gene expression	IDA	23839946
GO:0010628	Process	Positive regulation of gene expression	IDA	23388056, 26491108
GO:0010629	Process	Negative regulation of gene expression	IDA	23388056
GO:0016020	Component	Membrane	IEA
GO:0030154	Process	Cell differentiation	IEA
GO:0030217	Process	T cell differentiation	IEA
GO:0030217	Process	T cell differentiation	ISS
GO:0035912	Process	Dorsal aorta morphogenesis	IEA
GO:0035912	Process	Dorsal aorta morphogenesis	ISS
GO:0035924	Process	Cellular response to vascular endothelial growth factor stimulus	IMP	20616313
GO:0043537	Process	Negative regulation of blood vessel endothelial cell migration	IEA
GO:0044344	Process	Cellular response to fibroblast growth factor stimulus	IDA	20616313
GO:0045746	Process	Negative regulation of Notch signaling pathway	IBA
GO:0045746	Process	Negative regulation of Notch signaling pathway	IEA
GO:0045746	Process	Negative regulation of Notch signaling pathway	ISS
GO:0045747	Process	Positive regulation of Notch signaling pathway	IEA
GO:0045747	Process	Positive regulation of Notch signaling pathway	ISS
GO:0048018	Function	Receptor ligand activity	IDA	23839946
GO:0048018	Function	Receptor ligand activity	IEA
GO:0048513	Process	Animal organ development	IEA
GO:0048731	Process	System development	IEA
GO:0050767	Process	Regulation of neurogenesis	IEA
GO:0060579	Process	Ventral spinal cord interneuron fate commitment	IMP	17728344
GO:0061074	Process	Regulation of neural retina development	IEA
GO:0061074	Process	Regulation of neural retina development	ISS
GO:0072554	Process	Blood vessel lumenization	IEA
GO:0090051	Process	Negative regulation of cell migration involved in sprouting angiogenesis	IDA	23388056
GO:0090051	Process	Negative regulation of cell migration involved in sprouting angiogenesis	IMP	20616313
GO:1903588	Process	Negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	IDA	23388056
GO:2000179	Process	Positive regulation of neural precursor cell proliferation	IEA
GO:2000179	Process	Positive regulation of neural precursor cell proliferation	ISS

Other IDs

• MIM: 605185
• HGNC: 2910
• e!Ensembl: ENSG00000128917

Protein

• UniProt ID: Q9NR61
• Protein name: Delta-like protein 4 (Drosophila Delta homolog 4) (Delta4)
• Protein function: Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essen
• PDB: 5MVX
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF07657	MNNL	27 → 89	N terminus of Notch ligand	Family
  PF01414	DSL	155 → 217	Delta serrate ligand	Domain
  PF00008	EGF	281 → 320	EGF-like domain	Domain
  PF00008	EGF	328 → 358	EGF-like domain	Domain
  PF00008	EGF	366 → 398	EGF-like domain	Domain
  PF12661	hEGF	411 → 432	Human growth factor-like EGF	Domain
  PF00008	EGF	444 → 474	EGF-like domain	Domain

• Tissue specificity: TISSUE SPECIFICITY: Expressed in vascular endothelium.
• Sequence:

  MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEPGCRTFFRV
  CLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIE
  AWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQTSTLTRLRYSYRVICSDNYY
  GDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTGEYCQQPICLSGCHEQNGYCSKPAECL
  CRPGWQGRLCNECIPHNGCRHGTCSTPWQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATC
  SNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCE
  HSTLSCADSPCFNGGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNR
  GPSRMCRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTS
  IDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSFPWVAVSLGVGLAV
  LLVLLGMVAVAVRQLRLRRPDDGSREAMNNLSDFQKDNLIPAAQLKNTNQKKELEVDCGL
  DKSNCGKQQNHTLDYNLAPGPLGRGTMPGKFPHSDKSLGEKAPLRLHSEKPECRISAICS
  PRDSMYQSVCLISEERNECVIATEV

• Sequence length: 685

Pathways

KEGG:

Endocrine resistance
Notch signaling pathway
Th1 and Th2 cell differentiation
Pathways in cancer
Chemical carcinogenesis - receptor activation
Breast cancer

Reactome:

Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
Constitutive Signaling by NOTCH1 HD Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
NOTCH2 Activation and Transmission of Signal to the Nucleus
NOTCH3 Activation and Transmission of Signal to the Nucleus

Associated diseases

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Adams-Oliver syndrome	Pathogenic; Likely pathogenic	rs796065350, rs796065348, rs796065351, rs796065347, rs796065346, rs796065345, rs796065344, rs61750844	RCV000190441 RCV000190439 RCV000190442 RCV000190438 RCV000190437 RCV000190436 RCV000190434 RCV000190435
Adams-Oliver syndrome 6	Likely pathogenic; Pathogenic	rs2140369593, rs796065350, rs796065348, rs796065347, rs796065346, rs796065344, rs61750844, rs2542549210, rs2542541193, rs2542541573, rs1555393027, rs1555393125, rs1247027543, rs1555393182, rs1596194950, rs1892853569, rs1373760209	RCV001775302 RCV000195289 RCV000195285 RCV000195284 RCV000195288 RCV000195286 RCV000195290 RCV003236682 RCV003991226 RCV004594934 RCV000662242 RCV000662243 RCV000662244 RCV000662234 RCV000985148 RCV001194629 RCV001526864
DLL4-related disorder	Pathogenic; Likely pathogenic	rs796065348, rs1357715175	RCV004730899 RCV003391425

Unknown
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Clear cell carcinoma of kidney	Uncertain significance	rs372893200	RCV005930651
Focal segmental glomerulosclerosis 9	Conflicting classifications of pathogenicity	rs374783170	RCV005863825
Lung cancer	Benign	rs61757617	RCV005904434
Malignant tumor of esophagus	Benign	rs61757617	RCV005904431
Ovarian serous cystadenocarcinoma	Benign	rs61757617	RCV005904432
Thyroid cancer, nonmedullary, 1	Benign	rs61757617	RCV005904433

Associations from Text Mining
Disease Name	Relationship Type	References
Adams Oliver syndrome	Associate	26299364, 29924900
Aortic Aneurysm Thoracic	Associate	23300792
Arthritis Rheumatoid	Associate	37796367
Biliary Atresia	Associate	32767570
Body Weight	Associate	24394305
Brain Edema	Associate	25121357
Breast Neoplasms	Associate	18681966, 20167860, 26472724, 27542210, 35953532, 36740988, 37993804
Carcinoma Adenoid Cystic	Associate	33469672
Carcinoma Hepatocellular	Associate	26443326, 30660174
Carcinoma Non Small Cell Lung	Associate	30593175
Carcinoma Pancreatic Ductal	Associate	25986715, 27755532
Carcinoma Renal Cell	Associate	23826258, 24931473
Castleman Disease	Associate	34686774
Colorectal Neoplasms	Associate	19844231, 26111775, 34487019
Death Sudden	Associate	34328347
Dissection Thoracic Aorta	Associate	23300792
Ectodermal Dysplasia	Associate	26299364
Edema	Associate	23787764
Endometrial Neoplasms	Associate	34564988
Familial cerebral cavernous malformation	Associate	23388056
Farber Lipogranulomatosis	Associate	20737536
Glioblastoma	Associate	23787764, 25121357, 26472724, 33249476
Glioma	Associate	21517260
Granuloma	Associate	24394305
Hand Foot and Mouth Disease	Stimulate	24939221
Heart Defects Congenital	Associate	34859965
Heart Failure	Associate	34328347
Hemangioma Cavernous Central Nervous System	Associate	23388056
Hereditary Breast and Ovarian Cancer Syndrome	Inhibit	27542210
Hyperplasia	Associate	26808710
Hypertrophy	Associate	26808710
Hypoxia	Stimulate	16219802, 19844231, 22275240, 35765115
Hypoxia	Associate	34666595
Hypoxia Brain	Associate	33249476, 36332389
Inflammatory Bowel Diseases	Associate	33436852
Inflammatory Breast Neoplasms	Associate	31145753
Leukemia Lymphocytic Chronic B Cell	Associate	20017807, 31616059
Li Fraumeni Syndrome	Associate	27542210
Lung Injury	Associate	32801053
Lung Neoplasms	Associate	26472724, 33787845
Lymphatic Metastasis	Associate	26111775, 30593175
Lymphatic Metastasis	Stimulate	26546434
Lymphoma B Cell	Associate	20017807
Lymphopenia	Associate	32556283
Neoplasm Metastasis	Associate	23826258, 24931473, 25957329, 26111775, 26241546, 26443326, 30593175
Neoplasm Metastasis	Stimulate	33469672, 34487019
Neoplasms	Associate	16219802, 19844231, 20737536, 23826258, 23898884, 24931473, 25121357, 25957329, 26111775, 26241546, 26472724, 27542210, 27755532, 30593175, 30660174, 32689909, 33469672, 34410967, 34487019, 34564988, 36332389
Obesity	Associate	34487019
Osteoglophonic dwarfism	Associate	37741572
Ovarian Neoplasms	Associate	37796700
Pancreatic Neoplasms	Associate	19258443, 27755532
Retinoblastoma	Associate	27661116
Ring Chromosome 20 Syndrome	Stimulate	37741572
Sarcoma Kaposi	Associate	19816565
Sick Sinus Syndrome	Associate	25986715
Stomach Neoplasms	Associate	23898884, 34410967, 34925644, 36071128
Tachycardia Atrioventricular Nodal Reentry	Associate	23898884
Thrombosis	Associate	26443326
Thyroid Cancer Papillary	Associate	26241546
Thyroid Neoplasms	Associate	26241546
Thyroiditis Subacute	Associate	24394305
Tuberculosis	Associate	32801053
Uterine Cervical Neoplasms	Associate	26546434, 36973995
Varicose Veins	Associate	26808710
Virus Diseases	Associate	19816565