Editors' ChoiceENDOCYTOSIS AND SIGNALING

Delta's Circuitous Route to Notch

Science's STKE  26 Oct 2004:
Vol. 2004, Issue 256, pp. tw389
DOI: 10.1126/stke.2562004tw389

The Notch signaling pathway is highly conserved in metazoans and regulates a variety of cell fates during development. The Notch transmembrane proteins are receptors for transmembrane ligands of the Delta/Serrate/Lag2 family. It is thought that cells expressing ligands serve as signal senders that stimulate adjacent signal-receiving cells bearing Notch receptors. Less well understood is the suggestion that activation of Notch requires endocytosis of ligands by signal-sending cells. Two groups have now confirmed this notion in Drosophila studies. Overstreet et al. demonstrate that in the developing Drosophila eye, Liquid facets (Lqf), the sole ortholog of mammalian endocytic protein Epsin1, is required for Delta-Notch signaling. Epsins are cargo-selective adaptors that link mono-ubiquitinated cell surface proteins with the endocytic machinery. Loss of Lqf expression caused a phenotype similar to that in clones lacking Delta function in the signaling cells. Expression of Fat facets (Faf), which deubiquitinates Lqf, and Neuralized (Neur), which ubiquitinates Delta, was required for Delta endocytosis and Delta-Notch signaling. Wang and Struhl observed that overexpression of Delta failed to rescue the loss-of-function phenotype in developing Drosophila wing cells lacking Lqf. Adjacent Notch-expressing cells failed to become activated and turn on target genes. However, wild-type cells expressing ectopic Delta could activate Notch in adjacent cells that lack Lqf, which indicates that the adaptor protein is not essential in signal-receiving cells to respond to ligand. The authors show that mono-ubiquitination of Delta by Neur allows Lqf to associate with the ligand and target it for an endocytic pathway that is required for signaling activity. They propose that endocytic recycling of Delta may be required for ligands to be converted into activated forms.

E. Overstreet, E. Fitch, J. A. Fischer, Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells. Development 131, 5355-5366 (2004). [Abstract] [Full Text]

W. Wang, G. Struhl, Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development 131, 5367-5380 (2004). [Abstract] [Full Text]