Journal
DEVELOPMENTAL CELL
Volume 15, Issue 5, Pages 762-772Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2008.09.002
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Funding
- BBSRC
- BBSRC [BB/E002285/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E002285/1, BB/C503162/1] Funding Source: researchfish
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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.
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