Why is delta endocytosis required for effective activation of notch?

Abstract

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.

Figure 1. Basic Notch Signaling Pathway

During maturation Notch undergoes Furin-dependent S1 cleavage. Following interaction with Delta, Notch undergoes metalloprotease-dependent S2 cleavage. The Notch Extracellular Domain (NECD) is released and the Notch Extracellular Truncated (NEXT) fragment that remains is a substrate for a gamma-secretase complex that releases the Notch Intracellular Domain (NICD). NICD functions as a transcriptional activator in a complex with CSL proteins and Mastermind (MAM) to activate target hairy E(spl) related (her) genes.

Figure 2. Models for the role of Delta endocytosis

A, , Delta endocytosis facilitates Notch S2 cleavage. B-D, Delta endocytosis and recycling returns a Delta that is more effective at interacting with Notch. B, Recycling returns Delta to the surface in a microdomain where it is clustered, associated with co-factors (yellow trapezoids), or with modifications (red asterisk) of the extracellular domain that make Delta interactions with Notch more effective. C, Following endocytosis Delta is internalized in Multi Vesicular Bodies (MVBs) from which packets of clustered Delta are released as exosomes. D, Delta re-sensitization. Following endocytosis, the Delta-NECD complex dissociates, and unbound Delta returns to the surface via the recycling endosome for another round of interaction with Notch. NECD traffics to the late endosome and is eventually degraded in the lysosome.