Delta-like ligand 3 (DLL3) is a unique member of the DSL (Delta/Serrate/Lag-2) family in the Notch signaling pathway. Unlike canonical Notch ligands, DLL3 primarily functions as a cis-inhibitor rather than activating Notch signaling in neighboring cells. Its overexpression in neuroendocrine tumors, such as small cell lung cancer, inhibits Notch pathway activity, sustains stem-like properties, and promotes tumor progression. However, the structural basis by which DLL3 modulates Notch signaling remains incompletely understood.
To dissect the functional contributions of individual DLL3 domains, researchers have generated DLL1-DLL3 chimeric ligands and systematically evaluated their signaling activities via overexpression in CHO cells. These studies revealed that differences in the DSL domains, EGF repeats, and intracellular domains (ICDs) collectively contribute to the biochemical non-equivalence between DLL1 and DLL3. Notably, chimeras containing the DLL1 N-terminal portion including the DSL domain together with the DLL3 transmembrane and flanking intra- and extracellular sequences exhibited altered intracellular retention. These findings indicate that the DSL domain acts in concert with other regions to determine DLL3's unique inhibitory function and subcellular localization.
