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PMID:12794186
| Citation |
Six, E, Ndiaye, D, Laabi, Y, Brou, C, Gupta-Rossi, N, Israel, A and Logeat, F (2003) The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc. Natl. Acad. Sci. U.S.A. 100:7638-43 |
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| Abstract |
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. |
| Links |
PubMed PMC164639 Online version:10.1073/pnas.1230693100 |
| Keywords |
Amino Acid Sequence; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Line; Cell Nucleus/metabolism; Cells, Cultured; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Endopeptidases/metabolism; Flow Cytometry; Genetic Vectors; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Membrane Proteins/genetics; Membrane Proteins/metabolism; Metalloendopeptidases/metabolism; 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 |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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