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FLASH GENE
Symbol DLL4 contributors: mct - updated : 13-10-2016
HGNC name delta-like 4 (Drosophila)
HGNC id 2910
Corresponding disease
AOS6 Adams-Oliver syndrome 6
Location 15q15.1      Physical location : 41.221.530 - 41.231.257
Synonym name
  • notch ligand delta-2 precursor
  • Synonym symbol(s) hdelta2, MGC126344
    DNA
    TYPE functioning gene
    STRUCTURE 9.73 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 3420 - 685 - 2000 10837024
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessels   predominantly Homo sapiens
    Lymphoid/Immunethymus     Homo sapiens
    Nervousbrain    
    Respiratorylung    
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly Homo sapiens
    Connectivebone    Homo sapiens
    Epithelialbarrier/lining   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Lymphoid/Immuneepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
    one DSL domain, eight EGF repeats and a transmembrane domain
    isoforms Precursor a mature form of 71.9kDa
    HOMOLOGY
    interspecies homolog to Drosophila delta gene
    homolog to murine Dll4 (87.0pc)
    intraspecies homolog to JAG2
    Homologene
    FAMILY delta family of Notch ligands
    CATEGORY signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
    basic FUNCTION
  • notch receptor ligand playing a role in the Notch signaling pathway
  • activating NOTCH1 and NOTCH4
  • is essential for embryonic vascular development and arteriogenesis
  • may be involved in the tumor growth, via its action through the Notch signaling pathway
  • may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways
  • vascular-specific Notch ligand critical to normal vascular development
  • indispensable in thymic environment specific for T cell development
  • DLL4 and Jagged1 have opposing effects on angiogenesis
  • unique properties of DLL4 in supporting the combined T lineage and specific myeloid-lineage outcomes that underpin its function within the thymus
  • suppresses effector cell proliferation and enhances Th2 memory cell proliferation
  • DLL4/Notch signaling inhibits human terminal megakaryocytic differentiation
  • essential for the formation of mature vasculature (
  • specific role for DLL4 in the formation of bone marrow-derived pericyte/vascular smooth muscle cell (vSMC)
  • DLL1- and DLL4-mediated notch signaling are required for homeostasis of intestinal stem cells
  • DLL4 is directly activated by FOXN4 via phylogenetically conserved enhancers and DLL4 can partly mediate the FOXN4 function by serving as a major NOTCH1 ligand to expand the progenitor pool and limit photoreceptor production
  • role for DLL4 in the quantitative regulation of early hemato-vascular precursors, further indicating that it is also involved on the timely emergence of mesoderm in early embryogenesis
  • DLL4-NOTCH1 axis promotes potentially sustained macrophage activation via a positive feedback loop—a vicious cycle that represents mechanisms for uncontrolled macrophage activation typical of chronic inflammatory diseases
  • specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow
  • has an essential role in vascular development and angiogenesis
  • DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
  • DLL4-NOTCH1 signaling plays a central role in the shared mechanism for the pathogenesis of cardiometabolic disorders
  • ADAM10/DLL4 signaling is a major signaling pathway in ECs driving inflammatory events involved in inflammation and immune cell recruitment
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with Notch receptor
  • Dll4 is a physiological target of ZFP36L1 (binds to endogenous DLL4 mRNA, and represses mRNA expression without affecting its stability)
  • substantial DLL4 expression is maintained in the absence of KDR, while the FLT4 protein levels are strongly reduced
  • induces CCL2 expression in arteries and adipose tissues
  • is a key downstream target of PDCD10 in endothelial cells(CCM3/DLL4-Notch pathway serves as an important signalling for endothelial angiogenesis)
  • VEGFA inhibits EPHB4 and stimulates DLL4 expression in adult endothelial cells
  • SYNJ2BP, also known as ARIP2 interacted with the PDZ binding motif of DLL1 and DLL4, but not with the Notch ligand JAG1
  • mosaic expression of FOXN4 and proneural factors may serve as the trigger to initiate asymmetric DLL4-NOTCH1 and subsequent BMP/TGFB1 signaling events required for neuronal diversity in the V2 interneurons domain
  • SNAI1-DLL4/NOTCH1 axis controls embryonic vascular development
  • FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH1 or inhibition of NOTCH1 signal transduction
  • ADAM10-dependent regulation of DLL1 and DLL4 expression in association with changes in HES1 and HEY1 expression
  • DLL4 and JAG1 mediated NR4A1-induced angiogenic responses and signaling molecules, but not the expression of integrins
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) AOS6
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in breast cancer, endothelial DLL4 expression was a statistically significant multivariate prognostic factor
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerangiogenesis 
    may be a novel therapeutic target for the inhibition of vasculogenesis
    cancer  
    DLL4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors
    cancerdigestivecolon
    targeting DLL4-Notch signaling for improved treatment of colorectal patients with activating KRAS mutations
    diabetemetabolic syndrom 
    therapeutic target in cardiometabolic disorders
    cardiovascularaquired 
    blockade of DLL4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat
    diabetemetabolic syndrom 
    blockade of DLL4 by a neutralizing antibody attenuates key features typical of cardiovascular and metabolic diseases, such as accumulation of activated macrophages in arteries and fat
    ANIMAL & CELL MODELS