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Q9NR61

- DLL4_HUMAN

UniProt

Q9NR61 - DLL4_HUMAN

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Protein

Delta-like protein 4

Gene
DLL4, UNQ1895/PRO4341
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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 is 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.2 Publications

GO - Molecular functioni

  1. calcium ion binding Source: InterPro
  2. Notch binding Source: ProtInc

GO - Biological processi

  1. angiogenesis Source: BHF-UCL
  2. blood circulation Source: ProtInc
  3. blood vessel lumenization Source: Ensembl
  4. blood vessel remodeling Source: BHF-UCL
  5. cardiac atrium morphogenesis Source: BHF-UCL
  6. cardiac ventricle morphogenesis Source: BHF-UCL
  7. cellular response to fibroblast growth factor stimulus Source: UniProtKB
  8. cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
  9. dorsal aorta morphogenesis Source: BHF-UCL
  10. negative regulation of cell migration involved in sprouting angiogenesis Source: UniProtKB
  11. negative regulation of cell proliferation Source: UniProtKB
  12. negative regulation of endothelial cell migration Source: UniProtKB
  13. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  14. Notch receptor processing Source: Reactome
  15. Notch signaling involved in heart development Source: BHF-UCL
  16. Notch signaling pathway Source: Reactome
  17. patterning of blood vessels Source: BHF-UCL
  18. pericardium morphogenesis Source: BHF-UCL
  19. positive regulation of neural precursor cell proliferation Source: UniProtKB
  20. regulation of neural retina development Source: UniProtKB
  21. regulation of neurogenesis Source: Ensembl
  22. signal transduction Source: ProtInc
  23. ventral spinal cord interneuron fate commitment Source: UniProtKB
  24. ventricular trabecula myocardium morphogenesis Source: BHF-UCL
  25. visual perception Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Angiogenesis, Differentiation, Neurogenesis, Notch signaling pathway, Sensory transduction, Vision

Enzyme and pathway databases

ReactomeiREACT_118614. Activated NOTCH1 Transmits Signal to the Nucleus.
REACT_118636. Signaling by NOTCH4.
REACT_118862. Signaling by NOTCH3.
REACT_160089. Constitutive Signaling by NOTCH1 HD Domain Mutants.
REACT_160106. Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant.
REACT_160205. NOTCH2 Activation and Transmission of Signal to the Nucleus.
REACT_160243. Constitutive Signaling by NOTCH1 PEST Domain Mutants.
REACT_160254. Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
SignaLinkiQ9NR61.

Names & Taxonomyi

Protein namesi
Recommended name:
Delta-like protein 4
Alternative name(s):
Drosophila Delta homolog 4
Short name:
Delta4
Gene namesi
Name:DLL4
ORF Names:UNQ1895/PRO4341
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 15

Organism-specific databases

HGNCiHGNC:2910. DLL4.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini27 – 529503Extracellular Reviewed predictionAdd
BLAST
Transmembranei530 – 55021Helical; Reviewed predictionAdd
BLAST
Topological domaini551 – 685135Cytoplasmic Reviewed predictionAdd
BLAST

GO - Cellular componenti

  1. integral component of membrane Source: UniProtKB-KW
  2. plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA27366.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 26261 PublicationAdd
BLAST
Chaini27 – 685659Delta-like protein 4PRO_0000007512Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi108 – 1081N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi175 ↔ 184 By similarity
Glycosylationi183 – 1831N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi188 ↔ 200 By similarity
Glycosylationi205 – 2051N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi208 ↔ 217 By similarity
Disulfide bondi222 ↔ 233 By similarity
Disulfide bondi226 ↔ 239 By similarity
Disulfide bondi241 ↔ 250 By similarity
Disulfide bondi253 ↔ 264 By similarity
Disulfide bondi259 ↔ 270 By similarity
Disulfide bondi272 ↔ 281 By similarity
Disulfide bondi288 ↔ 300 By similarity
Disulfide bondi294 ↔ 310 By similarity
Disulfide bondi312 ↔ 321 By similarity
Disulfide bondi328 ↔ 339 By similarity
Disulfide bondi333 ↔ 348 By similarity
Disulfide bondi350 ↔ 359 By similarity
Disulfide bondi366 ↔ 377 By similarity
Disulfide bondi371 ↔ 388 By similarity
Disulfide bondi390 ↔ 399 By similarity
Glycosylationi393 – 3931N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi406 ↔ 417 By similarity
Disulfide bondi411 ↔ 426 By similarity
Disulfide bondi428 ↔ 437 By similarity
Disulfide bondi444 ↔ 455 By similarity
Disulfide bondi449 ↔ 464 By similarity
Disulfide bondi466 ↔ 475 By similarity
Disulfide bondi484 ↔ 495 By similarity
Disulfide bondi489 ↔ 506 By similarity
Disulfide bondi508 ↔ 517 By similarity

Post-translational modificationi

Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation By similarity.

Keywords - PTMi

Disulfide bond, Glycoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9NR61.
PRIDEiQ9NR61.

Expressioni

Tissue specificityi

Expressed in vascular endothelium.

Gene expression databases

BgeeiQ9NR61.
CleanExiHS_DLL4.
GenevestigatoriQ9NR61.

Organism-specific databases

HPAiHPA023392.

Interactioni

Subunit structurei

Binds to Notch-1 and Notch-4 By similarity.

Protein-protein interaction databases

STRINGi9606.ENSP00000249749.

Structurei

3D structure databases

ProteinModelPortaliQ9NR61.
SMRiQ9NR61. Positions 27-520.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini173 – 21745DSLAdd
BLAST
Domaini218 – 25134EGF-like 1Add
BLAST
Domaini252 – 28231EGF-like 2Add
BLAST
Domaini284 – 32239EGF-like 3Add
BLAST
Domaini324 – 36037EGF-like 4Add
BLAST
Domaini362 – 40039EGF-like 5Add
BLAST
Domaini402 – 43837EGF-like 6Add
BLAST
Domaini440 – 47637EGF-like 7Add
BLAST
Domaini480 – 51839EGF-like 8Add
BLAST

Domaini

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

Sequence similaritiesi

Contains 1 DSL domain.
Contains 8 EGF-like domains.

Keywords - Domaini

EGF-like domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG249767.
HOGENOMiHOG000267024.
HOVERGENiHBG007139.
InParanoidiQ9NR61.
KOiK06051.
OMAiLPFNFTW.
OrthoDBiEOG7GQXZ5.
PhylomeDBiQ9NR61.
TreeFamiTF351835.

Family and domain databases

InterProiIPR001774. DSL.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR009030. Growth_fac_rcpt_N_dom.
IPR011651. Notch_ligand_N.
[Graphical view]
PfamiPF01414. DSL. 1 hit.
PF00008. EGF. 4 hits.
PF12661. hEGF. 2 hits.
PF07657. MNNL. 1 hit.
[Graphical view]
SMARTiSM00051. DSL. 1 hit.
SM00181. EGF. 6 hits.
SM00179. EGF_CA. 2 hits.
[Graphical view]
SUPFAMiSSF57184. SSF57184. 1 hit.
PROSITEiPS00010. ASX_HYDROXYL. 1 hit.
PS51051. DSL. 1 hit.
PS00022. EGF_1. 8 hits.
PS01186. EGF_2. 7 hits.
PS50026. EGF_3. 8 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9NR61-1 [UniParc]FASTAAdd to Basket

« Hide

MAAASRSASG WALLLLVALW QQRAAGSGVF QLQLQEFINE RGVLASGRPC    50
EPGCRTFFRV CLKHFQAVVS PGPCTFGTVS TPVLGTNSFA VRDDSSGGGR 100
NPLQLPFNFT WPGTFSLIIE AWHAPGDDLR PEALPPDALI SKIAIQGSLA 150
VGQNWLLDEQ TSTLTRLRYS YRVICSDNYY GDNCSRLCKK RNDHFGHYVC 200
QPDGNLSCLP GWTGEYCQQP ICLSGCHEQN GYCSKPAECL CRPGWQGRLC 250
NECIPHNGCR HGTCSTPWQC TCDEGWGGLF CDQDLNYCTH HSPCKNGATC 300
SNSGQRSYTC TCRPGYTGVD CELELSECDS NPCRNGGSCK DQEDGYHCLC 350
PPGYYGLHCE HSTLSCADSP CFNGGSCRER NQGANYACEC PPNFTGSNCE 400
KKVDRCTSNP CANGGQCLNR GPSRMCRCRP GFTGTYCELH VSDCARNPCA 450
HGGTCHDLEN GLMCTCPAGF SGRRCEVRTS IDACASSPCF NRATCYTDLS 500
TDTFVCNCPY GFVGSRCEFP VGLPPSFPWV AVSLGVGLAV LLVLLGMVAV 550
AVRQLRLRRP DDGSREAMNN LSDFQKDNLI PAAQLKNTNQ KKELEVDCGL 600
DKSNCGKQQN HTLDYNLAPG PLGRGTMPGK FPHSDKSLGE KAPLRLHSEK 650
PECRISAICS PRDSMYQSVC LISEERNECV IATEV 685
Length:685
Mass (Da):74,605
Last modified:October 1, 2000 - v1
Checksum:i6CF89D3C220ACC89
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF253468 mRNA. Translation: AAF76427.1.
AB036931 mRNA. Translation: BAB16085.1.
AB043894 mRNA. Translation: BAB18581.1.
AY358894 mRNA. Translation: AAQ89253.1.
BC106950 mRNA. Translation: AAI06951.1.
AF279305 mRNA. Translation: AAF81912.1.
CCDSiCCDS45232.1.
PIRiJC7570.
RefSeqiNP_061947.1. NM_019074.3.
UniGeneiHs.511076.

Genome annotation databases

EnsembliENST00000249749; ENSP00000249749; ENSG00000128917.
GeneIDi54567.
KEGGihsa:54567.
UCSCiuc001zng.2. human.

Polymorphism databases

DMDMi13431490.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF253468 mRNA. Translation: AAF76427.1 .
AB036931 mRNA. Translation: BAB16085.1 .
AB043894 mRNA. Translation: BAB18581.1 .
AY358894 mRNA. Translation: AAQ89253.1 .
BC106950 mRNA. Translation: AAI06951.1 .
AF279305 mRNA. Translation: AAF81912.1 .
CCDSi CCDS45232.1.
PIRi JC7570.
RefSeqi NP_061947.1. NM_019074.3.
UniGenei Hs.511076.

3D structure databases

ProteinModelPortali Q9NR61.
SMRi Q9NR61. Positions 27-520.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

STRINGi 9606.ENSP00000249749.

Polymorphism databases

DMDMi 13431490.

Proteomic databases

PaxDbi Q9NR61.
PRIDEi Q9NR61.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000249749 ; ENSP00000249749 ; ENSG00000128917 .
GeneIDi 54567.
KEGGi hsa:54567.
UCSCi uc001zng.2. human.

Organism-specific databases

CTDi 54567.
GeneCardsi GC15P041221.
HGNCi HGNC:2910. DLL4.
HPAi HPA023392.
MIMi 605185. gene.
neXtProti NX_Q9NR61.
PharmGKBi PA27366.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG249767.
HOGENOMi HOG000267024.
HOVERGENi HBG007139.
InParanoidi Q9NR61.
KOi K06051.
OMAi LPFNFTW.
OrthoDBi EOG7GQXZ5.
PhylomeDBi Q9NR61.
TreeFami TF351835.

Enzyme and pathway databases

Reactomei REACT_118614. Activated NOTCH1 Transmits Signal to the Nucleus.
REACT_118636. Signaling by NOTCH4.
REACT_118862. Signaling by NOTCH3.
REACT_160089. Constitutive Signaling by NOTCH1 HD Domain Mutants.
REACT_160106. Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant.
REACT_160205. NOTCH2 Activation and Transmission of Signal to the Nucleus.
REACT_160243. Constitutive Signaling by NOTCH1 PEST Domain Mutants.
REACT_160254. Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
SignaLinki Q9NR61.

Miscellaneous databases

GeneWikii DLL4.
GenomeRNAii 54567.
NextBioi 57056.
PROi Q9NR61.
SOURCEi Search...

Gene expression databases

Bgeei Q9NR61.
CleanExi HS_DLL4.
Genevestigatori Q9NR61.

Family and domain databases

InterProi IPR001774. DSL.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR009030. Growth_fac_rcpt_N_dom.
IPR011651. Notch_ligand_N.
[Graphical view ]
Pfami PF01414. DSL. 1 hit.
PF00008. EGF. 4 hits.
PF12661. hEGF. 2 hits.
PF07657. MNNL. 1 hit.
[Graphical view ]
SMARTi SM00051. DSL. 1 hit.
SM00181. EGF. 6 hits.
SM00179. EGF_CA. 2 hits.
[Graphical view ]
SUPFAMi SSF57184. SSF57184. 1 hit.
PROSITEi PS00010. ASX_HYDROXYL. 1 hit.
PS51051. DSL. 1 hit.
PS00022. EGF_1. 8 hits.
PS01186. EGF_2. 7 hits.
PS50026. EGF_3. 8 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Dll4, a novel Notch ligand expressed in arterial endothelium."
    Shutter J.R., Scully S., Fan W., Richards W.G., Kitajewski J., Deblandre G.A., Kintner C.R., Stark K.L.
    Genes Dev. 14:1313-1318(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Brain.
  2. "Human Delta-2, Notch ligand gene."
    Sakano S.
    Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "Molecular cloning of Delta-4, a new mouse and human Notch ligand."
    Yoneya T., Tahara T., Nagao K., Yamada Y., Yamamoto T., Miyatani S., Nishikawa M.
    J. Biochem. 129:27-34(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
  6. "Signal peptide prediction based on analysis of experimentally verified cleavage sites."
    Zhang Z., Henzel W.J.
    Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 27-41.
  7. "A novel Delta gene expressed in embryonic and tumour vasculature."
    Mailhos C., Modlich U., Lewis J., Harris A., Bicknell R., Ish-Horowicz D.
    Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-685.
    Tissue: Placenta.
  8. "A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool."
    Del Barrio M.G., Taveira-Marques R., Muroyama Y., Yuk D.I., Li S., Wines-Samuelson M., Shen J., Smith H.K., Xiang M., Rowitch D., Richardson W.D.
    Development 134:3427-3436(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN NEUROGENESIS.
  9. "Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis."
    Brutsch R., Liebler S.S., Wustehube J., Bartol A., Herberich S.E., Adam M.G., Telzerow A., Augustin H.G., Fischer A.
    Circ. Res. 107:592-601(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN ANGIOGENESIS.

Entry informationi

Entry nameiDLL4_HUMAN
AccessioniPrimary (citable) accession number: Q9NR61
Secondary accession number(s): Q3KP23, Q9NQT9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: October 1, 2000
Last modified: September 3, 2014
This is version 134 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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