FOCAL POINT Sophie Hamel (right) and François Schweisguth (left), together with Jacques Fantini, demonstrate that glycosphingolipids (GSLs) promote Notch signaling by boosting endocytosis of the ligands Delta and Serrate. Ligand endocytosis—a prerequisite for receptor activation—is inhibited by a mutant version of the E3 ubiquitin ligase Mindbomb, resulting in decreased Notch signaling and an abnormal wing shape (left). Endocytosis—and Notch activity—is restored by overexpressing an enzyme that synthesizes the GSL N5 (right). Delta and Serrate bind GSLs directly, suggesting that their endocytosis may be stimulated by clustering into lipid raft–like membrane domains.