DLL4

Official Full Name

delta like canonical Notch ligand 4

Organism

Homo sapiens

GeneID

54567

Background

This 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]

Synonyms

AOS6; delta4; hdelta2;

Protein Sequence

MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEPGCRTFFRVCLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIEAWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQTSTLTRLRYSYRVICSDNYYGDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTGEYCQQPICLSGCHEQNGYCSKPAECLCRPGWQGRLCNECIPHNGCRHGTCSTPWQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATCSNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCEHSTLSCADSPCFNGGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNRGPSRMCRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTSIDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSFPWVAVSLGVGLAVLLVLLGMVAVAVRQLRLRRPDDGSREAMNNLSDFQKDNLIPAAQLKNTNQKKELEVDCGLDKSNCGKQQNHTLDYNLAPGPLGRGTMPGKFPHSDKSLGEKAPLRLHSEKPECRISAICSPRDSMYQSVCLISEERNECVIATEV

Open

Disease

Colorectal cancer, Fallopian tube cancer, Ovarian cancer, Peritoneal cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

6 +

Discontinued Drug

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Detailed Information

Among the crucial ligands in the Notch signaling pathway is DLL4, Delta-like Canonical Notch Ligand 4. Belonging to the Notch ligand family, it is a homolog of the Drosophila delta gene distinguished by the DSL (Delta/Serrate/LAG-2) domain, epidermal growth factor (EGF)-like repeats, and transmembrane domain. Comprising 658 amino acids, mostly serving through the Notch signaling pathway to control cell fate and tissue development, the type I single-pass transmembrane protein encoded by the DLL4 gene is Especially in angiogenesis, tumor microenvironment control, and immunological modulation, DLL4 is essential in many physiological and pathological processes.

Structure and Function of DLL4 Protein

The DLL4 protein comprises a cytoplasmic region, a transmembrane area, and an extracellular region. Eight EGF-like repetitions found in its extracellular area attach to Notch receptors and cause signal transduction. Additionally, it includes a DSL domain, crucial for specific binding between DLL4 and Notch receptors. Upon binding, the intracellular region can be cleaved and the released fragment enters the nucleus to regulate a series of target gene transcriptions. The glycosylation sites and highly conserved regions of the DLL4 protein further enhance its stability and activity in the Notch signaling pathway.

Dll4 can activate the Notch1 and Notch4 receptors as a ligand in the Notch signaling pathway. This activation sets off a sequence of proteolytic events involving receptor cleavage mediated by ADAM10 and γ-secretase, therefore releasing the Notch intracellular domain (NICD). NICD moves to the nucleus where it binds with complexes of transcription factors to control target gene expression. DLL4 mainly preserves normal vascular growth and function in angiogenesis by negatively controlling endothelial cell proliferation and migration and by preventing aberrant vessel sprouting.

Figure 1 depicts the Dll4/Notch signaling process in endothelial cells, where activation by Dll and Jagged ligands triggers cleavage and nuclear translocation of the receptor's NICD, blocking CSL and activating transcription of downstream genes through Hes and Hey transcription factors. Figure 1. Dll4/Notch signaling in the endothelial cells. (Lobov I, et al., 2018)

Expression of DLL4 is highly specific, primarily concentrated in endothelial cells, lymphatic endothelial cells, adipocytes, and intestinal goblet cells, with notably strong expression in tip cells of new blood vessels. Furthermore, DLL4 is found to be abnormally overexpressed in various tumor tissues, including breast cancer, bladder cancer, colorectal cancer, liver cancer, ovarian cancer, and pancreatic cancer, correlating closely with dysregulated tumor angiogenesis.

Mostly found in endothelial cells, lymphatic endothelial cells, adipocytes, and intestinal goblet cells, expression of DLL4 is quite selective and clearly expressed in tip cells of new blood arteries. Moreover, DLL4 is reported to be unusually overexpressed in several tumor tissues, including breast cancer, bladder cancer, colorectal cancer, liver cancer, ovarian cancer, and pancreatic cancer, strongly related to dysregulated tumor angiogenesis.

Regulation of Angiogenesis by DLL4

DLL4 regulates the formation and differentiation of new blood vessels by binding to Notch1 and Notch4 receptors, activating downstream signaling pathways. In normal angiogenesis, DLL4 is specifically expressed in "tip" cells of new blood vessels, which use filopodia to sense angiogenic signals in the microenvironment such as VEGF (vascular endothelial growth factor). Activation of DLL4 inhibits excessive proliferation of neighboring "stalk" cells, thereby limiting abnormal vessel expansion and promoting branch formation. Additionally, DLL4/Notch signaling interacts with Wnt/Fzd, Ang/Tie2, VEGF-A, and other pathways to further coordinate vessel growth, differentiation, and stabilization.

In the tumor microenvironment, DLL4 upregulation activates the Notch1 signaling pathway, inhibiting excessive angiogenesis and leading to abnormal vasculature, such as forming non-functional vessels and reducing perfusion efficiency. This "non-productive" tumor angiogenesis restricts the oxygen and nutrient supply needed for tumor growth and alters the tumor microenvironment, enhancing tumor cell invasiveness. Targeting the DLL4/Notch signaling pathway has been shown to disrupt tumor angiogenesis, thereby inhibiting tumor growth and spread.

DLL4 Signaling Pathway and Retinal Vessel Development

DLL4 plays an irreplaceable role in retinal angiogenesis. Studies using mouse retina models indicate that DLL4 is mainly expressed postnatally, guiding retinal vessel growth and branching. The dynamic expression of DLL4 is directly regulated by VEGF: VEGF induces high DLL4 expression in tip cells, while DLL4 negatively regulates VEGF action by inhibiting excessive formation of tip cells. Additionally, DLL4 is also highly expressed in mature arteries and arterioles, contributing to the stability of the retinal vascular network.

Connections of DLL4 to Other Physiological and Pathological Processes

The DLL4-Notch signaling pathway regulates the immune system primarily by modulating interactions between dendritic cells and T cells. Studies have shown that DLL4 affects immune responses in chronic liver injury by regulating inflammatory factor expression in liver sinusoidal endothelial cells and Kupffer cells through Notch signaling. Moreover, in acute liver failure (ACLF), DLL4-Notch signaling is involved in regulating inflammatory responses and metabolic disorders, potentially improving liver microcirculation and promoting liver regeneration.

DLL4-Notch signaling is closely associated with lipid metabolism disorders. In models of acute liver failure, aberrant DLL4 expression affects lipid metabolism and inflammatory responses, exacerbating oxidative stress and inflammatory factor activation, leading to systemic inflammation and tissue damage.

DLL4-Notch signaling is essential for bile duct regeneration and repair; during acute liver damage, DLL4 controls cholangiocyte proliferation and differentiation, hence enhancing bile metabolism function.

References:

Zhou Q, Li B, Li J. DLL4-Notch signaling in acute-on-chronic liver failure: State of the art and perspectives. Life Sci. 2023 Mar 15;317:121438.
Lobov I, Mikhailova N. The Role of Dll4/Notch Signaling in Normal and Pathological Ocular Angiogenesis: Dll4 Controls Blood Vessel Sprouting and Vessel Remodeling in Normal and Pathological Conditions. J Ophthalmol. 2018 Jul 5;2018:3565292.

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