DLLs (Delta-like ligands, DLL1, DLL3, and DLL4) are ligands of the Notch signaling pathway, which are often dysregulated in tumors and influence tumor growth, tumor vasculature, and tumor immunity. The Notch signaling pathway is a relatively conserved pathway in human evolution, mainly controlling cell processes through cell-to-cell interactions.
In mammals, there are four Notch receptors (Notch 1-4) and five ligands (DLL1, DLL3, DLL4, Jagged1, Jagged2). After enzymatic cleavage in the Golgi apparatus, Notch receptors are transported to the cell surface and form transmembrane heterodimers. Upon interaction with Notch ligands on neighboring cells, cleavage of the intracellular domain of Notch ligands occurs, leading to the release of Notch intracellular domain (NICD) from the cell surface. NICD then translocates to the cell nucleus, binds to DNA-binding protein CSL (CBF-1), recruits MAML (Mastermind-like protein), and activates transcription of Notch-target genes, including the Hes and Hey families.
Prior to trafficking to the cell membrane, DLLs undergo O-fucosylation in the Golgi apparatus to either enhance or dampen the DLL-Notch signal. DLL binding EGF on the cell membrane activates the Notch signal through endocytosis. Upon endocytosis, DLLs are degraded by proteases or lysosomes, or recycled to the cell membrane surface. The degradation or recycling of endocytosed DLLs is controlled by ubiquitination of the DLL intracellular domain (DICD). Apart from activating the Notch signal, DLLs can also inhibit the Notch signal through multiple pathways.
