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Protein

Delta-like protein 4

Gene

DLL4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

  • calcium ion binding Source: InterPro
  • Notch binding Source: ProtInc

GO - Biological processi

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 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:2910. DLL4.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini27 – 529503ExtracellularSequence AnalysisAdd
BLAST
Transmembranei530 – 55021HelicalSequence AnalysisAdd
BLAST
Topological domaini551 – 685135CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA27366.

Polymorphism and mutation databases

BioMutaiDLL4.
DMDMi13431490.

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...)Sequence Analysis
Disulfide bondi175 ↔ 184By similarity
Glycosylationi183 – 1831N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi188 ↔ 200By similarity
Glycosylationi205 – 2051N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi208 ↔ 217By similarity
Disulfide bondi222 ↔ 233By similarity
Disulfide bondi226 ↔ 239By similarity
Disulfide bondi241 ↔ 250By similarity
Disulfide bondi253 ↔ 264By similarity
Disulfide bondi259 ↔ 270By similarity
Disulfide bondi272 ↔ 281By similarity
Disulfide bondi288 ↔ 300By similarity
Disulfide bondi294 ↔ 310By similarity
Disulfide bondi312 ↔ 321By similarity
Disulfide bondi328 ↔ 339By similarity
Disulfide bondi333 ↔ 348By similarity
Disulfide bondi350 ↔ 359By similarity
Disulfide bondi366 ↔ 377By similarity
Disulfide bondi371 ↔ 388By similarity
Disulfide bondi390 ↔ 399By similarity
Glycosylationi393 – 3931N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi406 ↔ 417By similarity
Disulfide bondi411 ↔ 426By similarity
Disulfide bondi428 ↔ 437By similarity
Disulfide bondi444 ↔ 455By similarity
Disulfide bondi449 ↔ 464By similarity
Disulfide bondi466 ↔ 475By similarity
Disulfide bondi484 ↔ 495By similarity
Disulfide bondi489 ↔ 506By similarity
Disulfide bondi508 ↔ 517By 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 27-518.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

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

Domaini

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

Sequence similaritiesi

Contains 1 DSL domain.PROSITE-ProRule annotation
Contains 8 EGF-like domains.PROSITE-ProRule annotation

Keywords - Domaini

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

Phylogenomic databases

eggNOGiNOG249767.
GeneTreeiENSGT00760000118786.
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

        10         20         30         40         50
MAAASRSASG WALLLLVALW QQRAAGSGVF QLQLQEFINE RGVLASGRPC
60 70 80 90 100
EPGCRTFFRV CLKHFQAVVS PGPCTFGTVS TPVLGTNSFA VRDDSSGGGR
110 120 130 140 150
NPLQLPFNFT WPGTFSLIIE AWHAPGDDLR PEALPPDALI SKIAIQGSLA
160 170 180 190 200
VGQNWLLDEQ TSTLTRLRYS YRVICSDNYY GDNCSRLCKK RNDHFGHYVC
210 220 230 240 250
QPDGNLSCLP GWTGEYCQQP ICLSGCHEQN GYCSKPAECL CRPGWQGRLC
260 270 280 290 300
NECIPHNGCR HGTCSTPWQC TCDEGWGGLF CDQDLNYCTH HSPCKNGATC
310 320 330 340 350
SNSGQRSYTC TCRPGYTGVD CELELSECDS NPCRNGGSCK DQEDGYHCLC
360 370 380 390 400
PPGYYGLHCE HSTLSCADSP CFNGGSCRER NQGANYACEC PPNFTGSNCE
410 420 430 440 450
KKVDRCTSNP CANGGQCLNR GPSRMCRCRP GFTGTYCELH VSDCARNPCA
460 470 480 490 500
HGGTCHDLEN GLMCTCPAGF SGRRCEVRTS IDACASSPCF NRATCYTDLS
510 520 530 540 550
TDTFVCNCPY GFVGSRCEFP VGLPPSFPWV AVSLGVGLAV LLVLLGMVAV
560 570 580 590 600
AVRQLRLRRP DDGSREAMNN LSDFQKDNLI PAAQLKNTNQ KKELEVDCGL
610 620 630 640 650
DKSNCGKQQN HTLDYNLAPG PLGRGTMPGK FPHSDKSLGE KAPLRLHSEK
660 670 680
PECRISAICS PRDSMYQSVC LISEERNECV IATEV
Length:685
Mass (Da):74,605
Last modified:October 1, 2000 - v1
Checksum:i6CF89D3C220ACC89
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

ProteinModelPortaliQ9NR61.
SMRiQ9NR61. Positions 27-518.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000249749.

Polymorphism and mutation databases

BioMutaiDLL4.
DMDMi13431490.

Proteomic databases

PaxDbiQ9NR61.
PRIDEiQ9NR61.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi54567.
GeneCardsiGC15P041221.
HGNCiHGNC:2910. DLL4.
HPAiHPA023392.
MIMi605185. gene.
neXtProtiNX_Q9NR61.
PharmGKBiPA27366.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG249767.
GeneTreeiENSGT00760000118786.
HOGENOMiHOG000267024.
HOVERGENiHBG007139.
InParanoidiQ9NR61.
KOiK06051.
OMAiLPFNFTW.
OrthoDBiEOG7GQXZ5.
PhylomeDBiQ9NR61.
TreeFamiTF351835.

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.

Miscellaneous databases

GeneWikiiDLL4.
GenomeRNAii54567.
NextBioi57056.
PROiQ9NR61.
SOURCEiSearch...

Gene expression databases

BgeeiQ9NR61.
CleanExiHS_DLL4.
GenevestigatoriQ9NR61.

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]
ProtoNetiSearch...

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: April 29, 2015
This is version 139 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.