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First published online March 24, 2005
doi: 10.1242/10.1242/dev.01789

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The roles of receptor and ligand endocytosis in regulating Notch signaling

CNRS UMR 8542, Ecole Normale Supérieure, 46, rue d'Ulm 75230 Paris cedex, France

View larger version (31K): [in a new window]   Fig. 1. Notch signaling involves regulated-intramembrane proteolysis. Upon ligand binding, N undergoes two successive proteolytic cleavages (Brown et al., 2000). The first cleavage at the S2 site is ligand induced and generates an activated membrane-bound form of N (blue) that is further processed at the S3 site by the -secretase complex. This leads to the release of the NICD. The association of the NICD with DNA-bound CSL factors disrupts CSL-co-repressor (R) complexes and promotes the assembly of CSL-co-activator (A) complexes, thereby mediating a transcriptional switch. DSL ligands (pink) can be similarly processed, first at extracellular sites (S2) and then at an intramembrane S3 site by the -secretase complex (see text for details). CSL, CBF1, Suppressor of Hairless, Lag-1; Dl, Delta; N, Notch; NECD, Notch extracellular domain; NICD, N intracellular domain; Ser, Serrate.

View larger version (31K): [in a new window]   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.

View larger version (40K): [in a new window]   Fig. 3. Models of how ligand endocytosis promotes N signaling. Three models have been proposed to resolve the paradox that N activation in the signal receiving cell requires the endocytosis of Dl and Ser/Jagged in the signal-sending cell, which removes the ligands from the cell surface where they have to reside to interact with N. (1) The endocytosis of Notch-bound DSL ligands might create pulling forces on N that induce conformational changes associated with the unmasking of the S2 cleavage site. (2,3) Newly synthesized inactive DSL ligands become active upon being trafficked through endosomal compartments. In model 2, internalized DSL ligands transit via the recycling endosomes (RE, see Box 1) where they would be activated by an as yet unknown post-translational modification (Wang and Struhl, 2004). In model 3, endocytosed DSL ligands are targeted inside the lumen of MVBs (see Box 2), leading either to their degradation upon maturation of the MVBs into lysosomes, or to the extracellular release of secreted vesicles, called exosomes, on the fusion of the MVBs with the plasma membrane. These models are not mutually exclusive. The pH gradient of vesicles is color-coded from neutral (pale yellow) to pH 5 (orange). CCP, clathrin-coated pit; CCV, clathrin-coated vesicle; ECV, endosomal carrier vesicles; LE, late endosome; Lys, lysosome; MVBs, multivesicular bodies; NICD, N intracellular domain; RE, recycling endosome; SE, sorting endosomes; U, ubiquitin.

View larger version (33K): [in a new window]   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.

View larger version (38K): [in a new window]   Fig. 5. Regulation of N signaling during asymmetric cell division. (A) The cell fate determinants Neur (blue) and Numb (pink) are unequally segregated during the asymmetric division of the sensory organ precursor cell (SOP or pI) in Drosophila and are inherited by the pIIb daughter cell. -Adaptin (green) binds to Numb and is enriched at the anterior cortex of the dividing pI cell. (B) In the pIIb cell, the interaction of Numb with -Adaptin has been proposed to promote clathrin-mediated endocytosis of either N and/or Sanpodo to endosomes (E). Neur binds Delta (Dl), ubiquitinates it and promotes its endocytosis in the pIIb cell. It is not known whether the endocytosis of Dl is AP2-dependent. The endocytosis of Dl in pIIb leads to the activation of N in the pIIa cell. A possible role of Wasp in endocytosis may be to promote Dl internalization.

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