Abstract
BACE1 is a type I transmembrane aspartyl protease that cleaves amyloid precursor protein at the β-secretase site to initiate the release of β-amyloid peptide. As a secretase, BACE1 also cleaves additional membrane-bound molecules by exerting various cellular functions. In this study, we showed that BACE1 can effectively shed the membrane-anchored signaling molecule Jagged 1 (Jag1).Wealso mapped the cleavage sites of Jag1 by ADAM10 and ADAM17. Although Jag1 shares a high degree of homology with Jag2 in the ectodomain region, BACE1 fails to cleave Jag2 effectively, indicating a selective cleavage of Jag1. Abolished cleavage of Jag1 in BACE1-null mice leads to enhanced astrogenesis and, concomitantly, reduced neurogenesis. This characterization provides biochemical evidence that the Jag1-Notch pathway is under the control of BACE1 activity
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism
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ADAM10 Protein
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ADAM17 Protein
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Animals
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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HEK293 Cells
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Jagged-2 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Mutant Strains
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Proteolysis*
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Rats
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction / physiology*
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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JAG2 protein, human
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Jag1 protein, mouse
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Jag1 protein, rat
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Jag2 protein, mouse
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Jag2 protein, rat
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Jagged-1 Protein
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Jagged-2 Protein
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Membrane Proteins
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Receptors, Notch
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Serrate-Jagged Proteins
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Bace1 protein, rat
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human
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ADAM10 protein, rat
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Adam10 protein, mouse
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse
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Adam17 protein, rat