The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

• DOI: 10.1007/s00018-011-0639-0
• Publication Date: 2011-03-03T01:39:26Z
• Authors: Maria Dolores Gut...; Alvaro Gilsanz; María Yáñez-Mó; Susana Ovalle; Esther M. Lafuente; Carmen Domínguez; Peter N. Monk; Isidoro González-...; Francisco Sánchez...; Carlos Cabañas
• Keywords: ADAM17; TACE; 0303 health sciences; Membrane Glycoproteins; Tetraspanins; ICAM-1; Tumor Necrosis Factor-alpha; TNF-a; Endothelial Cells; CD9; ADAM17 Protein; Intercellular Adhesion Molecule-1; Tetraspanin 29; Cell Line; ADAM Proteins; 03 medical and health sciences; Antigens, CD; Leukocytes; Humans; Gene Silencing

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.