2 research outputs found
The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9
ADAM17/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 ADAM17s. This work was supported by
grants BFU2007-66443/BMC and BFU2010-19144/BMC from Ministerio de Ciencia e Innovación, a grant from Fundación de
Investigación Médica Mutua Madrileña and by RETICS Program
RD08/0075-RIER (Red de Inflamacio´n y Enfermedades Reumáticas)
from Instituto de Salud Carlos III (to C.C.), a grant from Fundación de
Investigación Médica Mutua Madrileña (to M.D.G.L.), and grants
PI080794 from Instituto de Salud Carlos III (to M.Y-M) and
SAF2007-60578 from Ministerio de Ciencia e Innovación (to
E.M.L.). M.D.G.L. was supported by a contract associated to grant
SAF2004-01715 from Ministerio de Ciencia e Innovacio´n. S.O. was
supported by an I3P predoctoral Fellowship from Consejo Superior de
Investigaciones Científicas (CSIC) and by a contract associated to
grant BFU2007-66443/BMC from Ministerio de Ciencia e Innovacio´n. A.G. has been supported by a predoctoral Fellowship from
Instituto de Salud Carlos III and by grant BFU2007-66443/BMC from
Ministerio de Ciencia e Innovación.Peer reviewe