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Published online February 25, 2008
doi:10.1083/jcb.200708127
The Journal of Cell Biology, Vol. 180, No. 4, 755-762
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Vaccari et al.
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 Endosomal entry regulates Notch receptor activation in Drosophila melanogaster

Thomas Vaccari1, Han Lu1, Ritu Kanwar2, Mark E. Fortini2, and David Bilder1

1 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720
2 Center for Cancer Research, National Cancer Institute, Frederick, MD 21702

Correspondence to D. Bilder: bilder{at}berkeley.edu

Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that {gamma}-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation.

Abbreviations used in this paper: Avl, Avalanche; DAPT, N-(N-[3,5-difluorophenacetyl-L-alanyl])-S-phenylglycine t-butyl ester; DSL, Delta, Serrate, Lag-2; EE, early endosomes; ESCRT, endosomal sorting complex required for transport; FC, follicle cell; Hnt, Hindsight; Lqf, Liquid facets; MVB, multivesicular body; NECD, Notch extracellular domain; NEXT, Notch extracellular truncation; NICD, Notch intracellular domain; Shi, Shibire; Wg, Wingless; WT, wild type.


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