title: Exosome release of ADAM15 and the functional implications of human macrophage-derived ADAM15 exosomes.
abstract: A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin αvβ3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Hee Doo
authors.initials: HD
authors.lastname: Lee
authors.forename: Bon-Hun
authors.initials: BH
authors.lastname: Koo
authors.forename: Yeon Hyang
authors.initials: YH
authors.lastname: Kim
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Jeon
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kim
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000235:genetics; D005089:Exocytosis; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D019096:Vitronectin; D011493:Protein Kinase C; D051722:ADAM Proteins; C098660:ADAM15 protein, human; D013755:Tetradecanoylphorbol Acetate