title: Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway.
abstract: DSL ligands promote proteolysis of the Notch receptor, to release active Notch intracellular domain (N(ICD)). Conversely, the E3 ubiquitin ligase Deltex can activate ligand-independent Notch proteolysis and signaling. Here we show that Deltex effects require endocytic trafficking by HOPS and AP-3 complexes. Our data suggest that Deltex shunts Notch into an endocytic pathway with two possible endpoints. If Notch transits into the lysosome lumen, it is degraded. However, if HOPS and AP-3 deliver Notch to the limiting membrane of the lysosome, degradation of the Notch extracellular domain allows subsequent Presenilin-mediated release of N(ICD). This model accounts for positive and negative regulatory effects of Deltex in vivo. Indeed, we uncover HOPS/AP-3 contributions to Notch signaling during Drosophila midline formation and neurogenesis. We discuss ways in which these endocytic pathways may modulate ligand-dependent and -independent events, as a mechanism that can potentiate Notch signaling or dampen noise in the signaling network.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Marian
authors.initials: M
authors.lastname: Wilkin
authors.forename: Pajaree
authors.initials: P
authors.lastname: Tongngok
authors.forename: Nicole
authors.initials: N
authors.lastname: Gensch
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Clemence
authors.forename: Masato
authors.initials: M
authors.lastname: Motoki
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hori
authors.forename: Maiko
authors.initials: M
authors.lastname: Taniguchi-Kanai
authors.forename: Emily
authors.initials: E
authors.lastname: Franklin
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Martin
authors.initials: M
authors.lastname: Baron
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000378:metabolism*; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D033963:Adaptor Protein Complex 3; C086679:DX protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C497759:N protein, Drosophila; D051880:Receptors, Notch