RRC ID 57646
Author Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwanger RS, Bellen HJ.
Title A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.
Journal Science
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.
Volume 338(6111)
Pages 1229-32
Published 2012-11-30
DOI 10.1126/science.1228745
PII 338/6111/1229
PMID 23197537
PMC PMC3663443
MeSH Amino Acid Sequence Amino Acid Substitution Animals Calcium-Binding Proteins / metabolism* Cells, Cultured DNA Mutational Analysis Drosophila Proteins / genetics* Drosophila Proteins / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / metabolism* Epidermal Growth Factor / genetics Evolution, Molecular Humans Intercellular Signaling Peptides and Proteins / metabolism* Intracellular Signaling Peptides and Proteins / metabolism* Jagged-1 Protein Ligands Male Membrane Proteins / metabolism* Methionine / genetics Molecular Sequence Data Mutation Receptor, Notch2 / genetics Receptor, Notch2 / metabolism Receptors, Notch / genetics* Receptors, Notch / metabolism* Serrate-Jagged Proteins Tandem Repeat Sequences / genetics Valine / genetics X Chromosome / genetics
IF 41.063
Times Cited 60