Drosophila HOPS and AP-3 Complex Genes Are Required for a Deltex-Regulated Activation of Notch in the Endosomal Trafficking Pathway

DSL ligands promote proteolysis of the Notch receptor, to release active Notch intracellular domain (NICD). 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 comp...

Full description

Saved in:
Bibliographic Details
Published in:Developmental cell 2008-11, Vol.15 (5), p.762-772
Main Authors: Wilkin, Marian, Tongngok, Pajaree, Gensch, Nicole, Clemence, Sylvaine, Motoki, Masato, Yamada, Kenta, Hori, Kazuya, Taniguchi-Kanai, Maiko, Franklin, Emily, Matsuno, Kenji, Baron, Martin
Format: Article
Language:English
Subjects:
Adaptor Protein Complex 3 - metabolism
Animals
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
CELLBIO
Drosophila
Drosophila melanogaster - cytology
Drosophila melanogaster - metabolism
Drosophila Proteins - metabolism
Endosomes - metabolism
Fundamental and applied biological sciences. Psychology
Membrane Proteins - metabolism
Molecular and cellular biology
Multiprotein Complexes
Protein Transport
Receptors, Notch - metabolism
SIGNALING
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:DSL ligands promote proteolysis of the Notch receptor, to release active Notch intracellular domain (NICD). 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 NICD. 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.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2008.09.002