The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor

Evidence indicates that endosomal entry promotes signaling by the Notch receptor, but the mechanisms involved are not clear. In a search for factors that regulate Notch activation in endosomes, we isolated mutants in Drosophila genes that encode subunits of the vacuolar ATPase (V-ATPase) proton pump...

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Bibliographic Details
Published in:Development (Cambridge) Vol. 137; no. 11; p. 1825
Main Authors: Vaccari, Thomas, Duchi, Serena, Cortese, Katia, Tacchetti, Carlo, Bilder, David
Format: Journal Article
Language:English
Published: England 01.06.2010
Subjects:
Animals
Animals, Genetically Modified
Drosophila - genetics
Drosophila - growth & development
Drosophila - metabolism
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Endosomes - metabolism
Eye - growth & development
Eye - metabolism
Eye - ultrastructure
Genes, Insect
Hydrogen-Ion Concentration
Lysosomes - metabolism
Microscopy, Electron, Transmission
Mutation
Receptors, Notch - genetics
Receptors, Notch - metabolism
Signal Transduction
Vacuolar Proton-Translocating ATPases - genetics
Vacuolar Proton-Translocating ATPases - metabolism
ISSN:1477-9129, 1477-9129
Online Access:Get more information
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Summary:Evidence indicates that endosomal entry promotes signaling by the Notch receptor, but the mechanisms involved are not clear. In a search for factors that regulate Notch activation in endosomes, we isolated mutants in Drosophila genes that encode subunits of the vacuolar ATPase (V-ATPase) proton pump. Cells lacking V-ATPase function display impaired acidification of the endosomal compartment and a correlated failure to degrade endocytic cargoes. V-ATPase mutant cells internalize Notch and accumulate it in the lysosome, but surprisingly also show a substantial loss of both physiological and ectopic Notch activation in endosomes. V-ATPase activity is required in signal-receiving cells for Notch signaling downstream of ligand activation but upstream of gamma-secretase-dependent S3 cleavage. These data indicate that V-ATPase, probably via acidification of early endosomes, promotes not only the degradation of Notch in the lysosome but also the activation of Notch signaling in endosomes. The results also suggest that the ionic properties of the endosomal lumen might regulate Notch cleavage, providing a rationale for physiological as well as pathological endocytic control of Notch activity.
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ISSN:1477-9129
1477-9129
DOI:10.1242/dev.045484