DLL4

Delta-like protein 4 (DLL4, Delta4), a type I membrane-bound Notch ligand, is one of five known Notch ligands in mammals and interacts predominantly with Notch 1, which has a key role in vascular development. Recent studies yield substantial insights into the role of DLL4 in angiogenesis. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a 'brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. DLL4 is downstream of VEGF signaling and its activation triggers a negative feedback that restrains the effects of VEGF. Attenuation of DLL4/Notch signaling results in chaotic vascular network with excessive branching and sprouting. DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. In pathological conditions, such as cancer, DLL4 is up-regulated strongly in the tumour vasculature. Blockade of DLL4-mediated Notch signaling strikingly increases nonproductive angiogenesis, but significantly inhibits tumor growth in preclinical mouse models. In preclinical studies, blocking of DLL4/Notch signaling is associated with a paradoxical increase in tumor vessel density, yet causes marked growth inhibition due to functionally defective vasculature. Thus, DLL4 blockade holds promise as an additional strategy for angiogenesis-based cancer therapy.

DLL4 Related Areas

Signal Transduction>>Notch Signaling Pathway>>DLL4/Delta4

Stem Cell>>Notch Signaling Pathway>>DLL4/Delta4

DLL4 Alternative Names

DLL4, delta 4, MGC126344, hdelta2, delta ligand 4 [Homo sapiens]

Dll4, Delta4, RP23-46P4.8 [Mus musculus]

Summaries for DLL4

Entrez Gene summary for DLL4:

This DLL4 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]

OMIM - description for DLL4:

Notch (see 190198) signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development. DLL4 is a transmembrane ligand for Notch receptors that shows restricted expression to endothelial cells (ECs), in particular to arteries and capillaries, and is involved in vascular development (Suchting et al., 2007).

Wikipedia summary for DLL4:

Delta like ligand 4 is a protein that in humans is encoded by the DLL4 gene.

Human DLL4 Protein General Information

 

• Protein names: Drosophila Delta homolog 4, Short name=Delta4
• Sequence length: 685 AA.
• Domain: The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor.
• Sequence similarities: DLL4 contains 1 DSL domain. DLL4 contains 8 EGF-like domains.
• Post-translational modification: Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation
• Subunit structure: DLL4 binds to Notch-1 and Notch-4
• Subcellular location: Membrane; Single-pass type I membrane protein
• Tissue specificity: Expressed in vascular endothelium.

General information above from UniProt

Function for DLL4 Protein

UniProtKB:

DLL4 plays a role in the Notch signaling pathway. DLL4 activates Notch-1 and Notch-4

Genatlas:

• DLL4 is notch receptor ligand playing a role in the Notch signaling pathway
• DLL4 activates NOTCH1 and NOTCH4
• DLL4 is essential for embryonic vascular development and arteriogenesis
• DLL4 may be involved in the tumor growth, via its action through the Notch signaling pathway
• DLL4 may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways (Pubmed 18339870)
• vascular-specific Notch ligand critical to normal vascular development (Pubmed 18577711)
• DLL4 is indispensable in thymic environment specific for T cell development (Pubmed 18824583)
• DLL4 and Jagged1 have opposing effects on angiogenesis (Pubmed 19524514)
• unique properties of DLL4 in supporting the combined T lineage and specific myeloid-lineage outcomes that underpin its function within the thymus (Pubmed 20548034)
• DLL4 suppresses effector cell proliferation and enhances Th2 memory cell proliferation (Pubmed 20808960)
• DLL4/Notch signaling inhibits human terminal megakaryocytic differentiation (Pubmed 20829371)
• DLL4 is essential for the formation of mature vasculature (Pubmed 20944072)
• DLL4 has a specific role for DLL4 in the formation of bone marrow-derived pericyte/vascular smooth muscle cell (vSMC) (Pubmed 20944072)
• DLL1- and DLL4-mediated notch signaling are required for homeostasis of intestinal stem cells (Pubmed 21238454)

Homology for human DLL4

• homolog to Drosophila delta gene
• homolog to murine Dll4 (87.0pc)
• homolog to JAG2