| Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments. | |
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MedLine Citation:
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PMID: 12087104 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In murine L cells, treatment with calpeptin or calpain inhibitor III increased Abeta42, but not Abeta40, secretion in a dose-dependent fashion. This correlated with an increase in the levels of amyloid precursor protein (APP) carboxyl-terminal fragments (CTFs). Immunoprecipitation with novel mAbs directed against the carboxyl-terminus of APP or specific for the beta-cleaved CTF showed that generation of both alpha- and beta-cleaved CTFs increase proportionately following inhibition of calpains. Pulse-chase metabolic labeling confirmed that inhibiting calpains increases the production of alpha- and beta-cleaved APP metabolites. Immunolabeling showed greater betaCTF signal in calpeptin-treated cells, primarily in small vesicular compartments that were shown to be predominantly endosomal by colocalization with early endosomal antigen 1. A second mAb, which recognizes an extracellular/luminal epitope found on both APP and betaCTFs, gave more cell surface labeling of calpeptin-treated cells than control cells. Quantitative binding of this antibody confirmed that inhibiting calpains caused a partial redistribution of APP to the cell surface. These results demonstrate that 1) calpain inhibition results in a partial redistribution of APP to the cell surface, 2) this redistribution leads to an increase in both alpha- and beta-cleavage without changing the ratio of alphaCTFs/betaCTFs, and 3) the bulk of the betaCTFs in the cell are within early endosomes, confirming the importance of this compartment in APP processing. |
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Authors:
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Paul M Mathews; Ying Jiang; Stephen D Schmidt; Olivera M Grbovic; Marc Mercken; Ralph A Nixon |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2002-06-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 277 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2002 Sep |
Date Detail:
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Created Date: 2002-09-23 Completed Date: 2002-11-13 Revised Date: 2008-09-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 36415-24 Citation Subset: IM |
Affiliation:
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Nathan Kline Institute, Orangeburg, New York 10962, USA. mathews@nki.rfmh.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid beta-Protein Precursor
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metabolism* Animals Antibodies, Monoclonal / metabolism Blotting, Western Calpain / antagonists & inhibitors, metabolism* Cell Line Cell Membrane / metabolism* Dipeptides / antagonists & inhibitors, metabolism Dose-Response Relationship, Drug Endosomes / metabolism Enzyme-Linked Immunosorbent Assay Humans Hydrogen-Ion Concentration Mice Microscopy, Confocal Microscopy, Fluorescence Models, Genetic Mutation Precipitin Tests Protein Binding Protein Structure, Tertiary Time Factors Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein Precursor; 0/Antibodies, Monoclonal; 0/Dipeptides; 117591-20-5/calpeptin; EC 3.4.22.-/Calpain |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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