A disintegrin and metalloproteinase-10 (ADAM-10) mediates DN30 antibody-induced shedding of the met surface receptor.
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.
Schelter
Florian
F
Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, München, Germany.
Kobuch
Julia
J
Moss
Marcia L
ML
Becherer
J David
JD
Comoglio
Paolo M
PM
Boccaccio
Carla
C
Krüger
Achim
A
D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism*
D000906:Antibodies; D008565:Membrane Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human