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Q9NR61

- DLL4_HUMAN

UniProt

Q9NR61 - DLL4_HUMAN

Protein

Delta-like protein 4

Gene

DLL4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 135 (01 Oct 2014)
      Sequence version 1 (01 Oct 2000)
      Previous versions | rss
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    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

    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

    GO - Cellular componenti

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

    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...)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 27-520.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

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

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei530 – 55021HelicalSequence AnalysisAdd
    BLAST

    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.
    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

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    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

    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: October 1, 2014
    This is version 135 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