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Title

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

AuthorsGutiérrez-López, María Dolores CSIC; Gilsanz, Álvaro; Yáñez-Mó, María; Ovalle, Susana; Lafuente, Esther M.; Domínguez, Carmen CSIC ORCID; Monk, Peter N.; González-Álvaro, Isidoro; Sánchez-Madrid, Francisco; Cabañas, Carlos CSIC ORCID
KeywordsADAM17
Tetraspanins
CD9
TACE
TNF-a
ICAM-1
Issue Date2011
PublisherSpringer
CitationCellular and Molecular Life Sciences 68(19): 3275-3292
AbstractADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-a 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-a and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17
Publisher version (URL)http://dx.doi.org/10.1007/s00018-011-0639-0
URIhttp://hdl.handle.net/10261/74970
DOIhttp://dx.doi.org/10.1007/s00018-011-0639-0
ISSN1420-682X
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