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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2000-7-17
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pubmed:abstractText |
Gamma-secretase-like proteolysis at site 3 (S3), within the transmembrane domain, releases the Notch intracellular domain (NICD) and activates CSL-mediated Notch signaling. S3 processing occurs only in response to ligand binding; however, the molecular basis of this regulation is unknown. Here we demonstrate that ligand binding facilitates cleavage at a novel site (S2), within the extracellular juxtamembrane region, which serves to release ectodomain repression of NICD production. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or gamma-secretase inhibitors or by loss of presenilin 1, and inhibition of NEXT eliminates NICD production. Our data demonstrate that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to Notch activation.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Disintegrins,
http://linkedlifedata.com/resource/pubmed/chemical/Drosophila Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Metalloendopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Presenilin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Notch1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/kuzbanian protein, Drosophila
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1097-2765
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
5
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
197-206
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:10882062-Amino Acid Sequence,
pubmed-meshheading:10882062-Amyloid Precursor Protein Secretases,
pubmed-meshheading:10882062-Conserved Sequence,
pubmed-meshheading:10882062-Cysteine,
pubmed-meshheading:10882062-Disintegrins,
pubmed-meshheading:10882062-Drosophila Proteins,
pubmed-meshheading:10882062-Endopeptidases,
pubmed-meshheading:10882062-Ligands,
pubmed-meshheading:10882062-Membrane Proteins,
pubmed-meshheading:10882062-Metalloendopeptidases,
pubmed-meshheading:10882062-Mutation,
pubmed-meshheading:10882062-Peptide Fragments,
pubmed-meshheading:10882062-Presenilin-1,
pubmed-meshheading:10882062-Protein Processing, Post-Translational,
pubmed-meshheading:10882062-Receptor, Notch1,
pubmed-meshheading:10882062-Receptors, Cell Surface,
pubmed-meshheading:10882062-Signal Transduction,
pubmed-meshheading:10882062-Transcription Factors
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pubmed:year |
2000
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pubmed:articleTitle |
A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.
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pubmed:affiliation |
Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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