title: An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling.
abstract: Cell-to-cell communication via the Notch pathway is mediated between the membrane-bound Notch receptor and either of its canonical membrane-bound ligands Delta or Serrate. Notch ligands mediate receptor transactivation between cells and also mediate receptor cis-inhibition when Notch and ligand are co-expressed on the same cell. We demonstrate in Drosophila that removal of any of the EGF-like repeats (ELRs) 4, 5 or 6 results in a Serrate molecule capable of transactivating Notch but exhibiting little or no Notch cis-inhibition capacity. These forms of Serrate require Epsin (Liquid facets) to transduce a signal, suggesting that ELR 4-6-deficient ligands still require endocytosis for Notch activation. We also demonstrate that ELRs 4-6 are responsible for the dominant-negative effects of Serrate ligand forms that lack the intracellular domain and are therefore incapable of endocytosis in the ligand-expressing cell. We find that ELRs 4-6 of Serrate are conserved across species but do not appear to be conserved in Delta homologs.
authors.affiliation: Trinity College, Department of Biology, 300 Summit Street, Hartford, CT 06106, USA. robert.fleming@trincoll.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fleming
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hori
authors.forename: Anindya
authors.initials: A
authors.lastname: Sen
authors.forename: Gina V
authors.initials: GV
authors.lastname: Filloramo
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Langer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Obar
authors.forename: Spyros
authors.initials: S
authors.lastname: Artavanis-Tsakonas
authors.forename: Ayiti C
authors.initials: AC
authors.lastname: Maharaj-Best
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D005260:Female; D017353:Gene Deletion; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes; D014921:Wings, Animal / Q000166:cytology / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; C557617:GAL4 protein, Drosophila; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C114154:epsin