A disintegrin and metalloproteinase-10 (ADAM-10) mediates DN30 antibody-induced shedding of the met surface receptor

Florian Schelter, Julia Kobuch, Marcia L. Moss, J. David Becherer, Paolo M. Comoglio, Carla Boccaccio, Achim Krüger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)26335-26340
Number of pages6
JournalJournal of Biological Chemistry
Volume285
Issue number34
DOIs
Publication statusPublished - Aug 20 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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