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The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase.

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.

Pubmed ID: 12794186

Authors

  • Six E
  • Ndiaye D
  • Laabi Y
  • Brou C
  • Gupta-Rossi N
  • Israel A
  • Logeat F

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 24, 2003

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Cell Line
  • Cell Nucleus
  • Cells, Cultured
  • Chromatography, Gel
  • Electrophoresis, Polyacrylamide Gel
  • Endopeptidases
  • Flow Cytometry
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Metalloendopeptidases
  • Mice
  • Microscopy, Fluorescence
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Precipitin Tests
  • Presenilin-1
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transfection