title: A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.
abstract: Notch signaling affects many developmental and cellular processes and has been implicated in congenital disorders, stroke, and numerous cancers. The Notch receptor binds its ligands Delta and Serrate and is able to discriminate between them in different contexts. However, the specific domains in Notch responsible for this selectivity are poorly defined. Through genetic screens in Drosophila, we isolated a mutation, Notch(jigsaw), that affects Serrate- but not Delta-dependent signaling. Notch(jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (EGFr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 also exhibits defects in signaling of a mammalian Serrate homolog, Jagged1. Hence, an evolutionarily conserved valine in EGFr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Rana
authors.forename: Shinako
authors.initials: S
authors.lastname: Kakuda
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.forename: Vafa
authors.initials: V
authors.lastname: Bayat
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.forename: Gabriela
authors.initials: G
authors.lastname: David
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Haltiwanger
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008715:Methionine / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D020080:Tandem Repeat Sequences / Q000235:genetics; D014633:Valine / Q000235:genetics; D014960:X Chromosome / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D004815:Epidermal Growth Factor; D008715:Methionine; D014633:Valine