Fig. 4. Models of how Dx and Su(dx) regulate N signaling. (A) Su(dx) and Nedd4 bind and ubiquitinate (Ubi) N. Drosophila Nedd4 and Su(Dx) interact with the PPSY endocytic motif of N via their WW domains, and promote the ubiquitination of N. Ubiquitination of N by Nedd4/Su(dx) leads to the endosomal degradation of N. Deltex (Dx) interacts with the Ankyrin (ANK) repeats of N and exhibits E3 ligase activity in vitro. However, it is not yet known whether Dx promotes the ubiquitination of N. It has been proposed that Su(Dx) and Nedd4 interact with the full-length N, as depicted here. Whether Dx interacts with full-length N or with the S2-cleaved form of N is not known. These interactions may occur at the plasma membrane or in endosomes. (B) Dx and Su(dx)/Nedd4 appear to act antagonistically to regulate N endosomal sorting. Upon arrival in sorting endosomes (SE), N may be targeted for degradation to a late endosomal, Rab7-GFP positive compartment. This sorting event appears to be regulated by Su(dx) and Nedd4. Dx may act antagonistically to Su(dx) and Nedd4 by sorting N towards a Rab11-GFP-positive compartment that may correspond to the recycling endosome (RE). This sorting event may promote a CSL- and DSL-independent activity of N. Localization studies have suggested that Su(dx)/Nedd4 and Dx are present in endosomes, but it is possible that they also act at the cell surface to mediate N endocytosis.