| A disintegrin and metalloproteinase-10 (ADAM-10) mediates DN30 antibody-induced shedding of the met surface receptor. | |
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MedLine Citation:
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PMID: 20554517 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Met, the tyrosine kinase receptor for the hepatocyte growth factor is a prominent regulator of cancer cell invasiveness and has emerged as a promising therapeutic target. Binding of the anti-Met monoclonal antibody DN30 to its epitope induces the proteolytic cleavage of Met, thereby impairing the invasive growth of tumors. The molecular mechanism controlling this therapeutic shedding process has so far been unknown. Here, we report that A Disintegrin And Metalloproteinase (ADAM)-10, but not ADAM-17, is required for DN30-induced Met shedding. Knockdown of ADAM-10 in different tumor cell lines or abrogation of its proteolytic activity by natural or synthetic inhibitors abolished Met down-regulation on the cell surface as well as reduction of Met activation. Moreover, hepatocyte growth factor-induced tumor cell migration and invasion were impaired upon ADAM-10 knockdown. Thus, the therapeutic effect of DN30 involves ADAM-10-dependent Met shedding, linking for the first time a specific metalloprotease to target therapy against a receptor tyrosine kinase. |
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Authors:
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Florian Schelter; Julia Kobuch; Marcia L Moss; J David Becherer; Paolo M Comoglio; Carla Boccaccio; Achim Krüger |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-16 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-16 Completed Date: 2010-09-30 Revised Date: 2012-06-04 |
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: 26335-40 Citation Subset: IM |
Affiliation:
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Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, München, Germany. |
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| MeSH Terms | |
Descriptor/Qualifier:
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ADAM Proteins
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physiology* Amyloid Precursor Protein Secretases / physiology* Antibodies / pharmacology, therapeutic use* Cell Line, Tumor Hepatocyte Growth Factor / pharmacology Humans Membrane Proteins / physiology* Neoplasm Invasiveness / prevention & control Neoplasm Metastasis / drug therapy, prevention & control Proto-Oncogene Proteins c-met / drug effects, metabolism* Receptors, Growth Factor / drug effects, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antibodies; 0/Membrane Proteins; 0/Receptors, Growth Factor; 67256-21-7/Hepatocyte Growth Factor; EC 2.7.10.1/MET protein, human; EC 2.7.10.1/Proto-Oncogene Proteins c-met; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.81/ADAM10 protein, human |
| Comments/Corrections | |
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