Delta-like ligand 3

Delta-like ligand 3 (DLL3) is a protein that in humans is encoded by the DLL3 gene. It is a member of the Delta/Serrate/LAG-2 (DSL) family of ligands that activate Notch signaling. Notch signaling is a highly conserved pathway that influences cell fate determination, proliferation, and apoptosis in a variety of cell types. DLL3 has a unique role in the pathway, primarily influencing neurogenesis and somitogenesis during embryonic development.

Function

DLL3 functions as a Notch receptor antagonist rather than an activator, which is atypical for DSL proteins. It is predominantly expressed in the developing central nervous system (CNS) and somites, suggesting its critical role in the segmentation of the paraxial mesoderm and neurodevelopment. Unlike other Notch ligands, DLL3 does not interact with Notch receptors at the cell surface. Instead, it modulates Notch signaling in a non-canonical manner, likely through intracellular interactions that affect the processing and trafficking of Notch receptors.

Clinical Significance

Mutations in the DLL3 gene are associated with congenital scoliosis due to its role in somitogenesis. Specifically, these mutations can lead to a rare autosomal recessive disorder known as Spondylocostal dysostosis, characterized by abnormal vertebral segmentation and rib malformations. The study of DLL3 and its interactions with the Notch signaling pathway offers potential therapeutic targets for manipulating this pathway in diseases characterized by aberrant Notch activity.

Research

Research on DLL3 is ongoing, particularly in the context of cancer. DLL3 expression has been found to be upregulated in certain types of neuroendocrine tumors, including small cell lung cancer (SCLC). This has led to the development of targeted therapies, such as antibody-drug conjugates (ADCs), that specifically target DLL3-expressing cancer cells. These therapies are in various stages of clinical trials and represent a promising area of cancer treatment.

See Also

• Notch signaling pathway
• Spondylocostal dysostosis
• Neuroendocrine tumor
• Antibody-drug conjugate