Endocytosis is extremely important for the activity of the developmentally crucial Notch signalling pathway. Upon binding to transmembrane ligands of the Delta/Serrate/Lag2 (DSL) family, the cell-surface receptor Notch is cleaved,allowing its cytosolic domain to enter the nucleus and activate target genes. Notch activation also seems to require DSL ligand endocytosis. Two groups now shed further light on this process and one reaches some surprising conclusions. On p. , Overstreet et al. show that Delta signalling in the developing Drosophila eye requires the activity of Liquid facets (Lqf), the Drosophilahomologue of epsin, an adaptor protein involved in clathrin-mediated endocytosis. They also show that in one Notch signalling event in the eye,Delta internalisation and signalling is promoted by Fat facets (Faf), which deubiquitinates Lqf, and by Neuralised (Neur), which ubiquitinates Delta. On p. , Wang and Struhl report that Lqf is required for cells to send, but not to receive, DSL signals and that internalisation of DSL signals may be the sole role of epsin in Drosophila. They show that mono-ubiquitination of DSL proteins by Neur allows Lqf to target DSL proteins to a special endocytic pathway that they must enter to signal. Both groups report that the bulk endocytosis of DSL proteins does not require Lqf, leading Wang and Struhl to propose that Lqf targets DSL proteins to a subclass of coated pits required for Notch activation or to an endocytic recycling pathway that converts DSL proteins into active ligands.
