A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands

Shinya Yamamoto, Wu-Lin Charng, Nadia A Rana, Shinako Kakuda, Manish Jaiswal, Vafa Bayat, Bo Xiong, Ke Zhang, Hector Sandoval, Gabriela David, Hao Wang, Robert S Haltiwanger, Hugo J Bellen

Research output: Contribution to journalArticle

65 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1229-32
Number of pages4
JournalScience (New York, N.Y.)
Volume338
Issue number6111
DOIs
StatePublished - Nov 30 2012

Keywords

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Calcium-Binding Proteins
  • Cells, Cultured
  • DNA Mutational Analysis
  • Drosophila Proteins
  • Drosophila melanogaster
  • Epidermal Growth Factor
  • Evolution, Molecular
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Male
  • Membrane Proteins
  • Methionine
  • Molecular Sequence Data
  • Mutation
  • Receptor, Notch2
  • Receptors, Notch
  • Tandem Repeat Sequences
  • Valine
  • X Chromosome
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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