The Sema domain of Met is necessary for receptor dimerization and activation.
Hepatocyte growth factor (HGF) binds the extracellular domain and activates the Met receptor to induce mitogenesis, morphogenesis, and motility. The extracellular domain of Met is comprised of Sema, PSI, and four IPT subdomains. We investigated the contribution of these subdomains to Met receptor dimerization. Our observations indicate that the Sema domain is necessary for dimerization in addition to HGF binding. Treatment of Met-overexpressing tumor cells with recombinant Sema in the presence or absence of HGF results in decreased Met-mediated signal transduction, cell motility, and migration, behaving in a manner similar to an antagonistic anti-Met Fab. These data suggest that the Sema domain of Met may not only represent a novel anticancer therapeutic target but also acts as a biotherapeutic itself.
Kong-Beltran
Monica
M
Department of Molecular Oncology, Genetech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Stamos
Jennifer
J
Wickramasinghe
Dineli
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D002465:Cell Movement; D003432:Cross-Linking Reagents; D019281:Dimerization; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met