Why is Delta endocytosis required for effective activation of Notch?

A number of recent studies have shown that endocytosis of Notch ligands is required for activation of Notch. There are at least two broad models that account for how Delta endocytosis in one cell might contribute to activation of Notch in the neighboring cell. The first class of models is related to the possibility that Delta endocytosis facilitates S2 cleavage and removal of the Notch extracellular domain, a critical step in Notch activation. A second class of models is related to the possibility that Delta ubiquitylation and endocytosis facilitates interactions between Delta and Notch. In the second set of models, Delta undergoes endocytosis and its subsequent trafficking back to the surface, following modifications or some change in the context in which it is presented, makes Delta a more effective ligand. Though it is still not clear how either or both mechanisms contribute, recent evidence points to the importance of both endocytosis and recycling in Delta signaling.