title: The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9.
abstract: ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Gutiérrez-López
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gilsanz
authors.forename: María
authors.initials: M
authors.lastname: Yáñez-Mó
authors.forename: Susana
authors.initials: S
authors.lastname: Ovalle
authors.forename: Esther M
authors.initials: EM
authors.lastname: Lafuente
authors.forename: Carmen
authors.initials: C
authors.lastname: Domínguez
authors.forename: Peter N
authors.initials: PN
authors.lastname: Monk
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Alvaro
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.forename: Carlos
authors.initials: C
authors.lastname: Cabañas
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000072198:ADAM17 Protein; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060245:Tetraspanin 29; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C554869:CD9 protein, human; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human