Fig. 2. Structure and function of E3 ubiquitin ligases involved in N signaling. Four families of E3 ubiquitin ligases have been described: the Ring finger family; the HECT (homologous to E6AP COOH terminus) family; the F-box and multi-subunit E3 ubiquitin ligases (SCF/Cullin); and the U-box-containing E3 ubiquitin ligases. Some members of the Ring finger family are part of multi-protein complexes that contain F-boxes. Members of three of these families (Ring finger, HECT, SCF/Cullin) have been involved in N signaling in Drosophila (Lai, 2002). The E3 ubiquitin ligases of the Ring finger and HECT families involved in the regulation of receptor and ligand endocytosis are shown in this figure. Not shown is SEL-10, a F-Box protein of a SCF (Skp1-Cul1-F-box-Rbx1)-type ubiquitin ligase, which was first identified as a negative regulator of lin-12 and which was recently shown to bind the nuclear form of activated N in a phosphorylation-dependent manner to promote its proteasome-mediated degradation (reviewed by Lai, 2002). HERC2, Hect (homologous to the E6-AP carboxyl terminus domain and RCC1-like domain 2); WWE, WWE domain (named after three of its conserved residues); ZnF ZZ, ZZ-type Zinc Finger; UBA, ubiquitin-associated domain.