Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila.
Ligands of the Delta/Serrate/Lag2 (DSL) family must normally be endocytosed in signal-sending cells to activate Notch in signal-receiving cells. DSL internalization and signaling are promoted in zebrafish and Drosophila, respectively, by the ubiquitin ligases Mind bomb (Mib) and Neuralized (Neur). DSL signaling activity also depends on Epsin, a conserved endocytic adaptor thought to target mono-ubiquitinated membrane proteins for internalization. Here, we present evidence that the Drosophila ortholog of Mib (Dmib) is required for ubiquitination and signaling activity of DSL ligands in cells that normally do not express Neur, and can be functionally replaced by ectopically expressed Neur. Furthermore, we show that both Dmib and Epsin are required in these cells for some of the endocytic events that internalize DSL ligands, and that the two Drosophila DSL ligands Delta and Serrate differ in their utilization of these Dmib- and Epsin-dependent pathways: most Serrate is endocytosed via the actions of Dmib and Epsin, whereas most Delta enters by other pathways. Nevertheless, only those Serrate and Delta proteins that are internalized via the action of Dmib and Epsin can signal. These results support and extend our previous proposal that mono-ubiquitination of DSL ligands allows them to gain access to a select, Epsin-dependent, endocytic pathway that they must normally enter to activate Notch.
Wang
Weidong
W
Howard Hughes Medical Institute, Department of Genetics and Development, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA.
Struhl
Gary
G
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002135:Calcium-Binding Proteins; D002450:Cell Communication; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004705:Endocytosis; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000145:classification / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; C064045:delta protein; C114154:epsin; C502570:Mib1 protein, Drosophila; D044767:Ubiquitin-Protein Ligases; C071006:neur protein, Drosophila