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and Epidermal Growth Factor1
,
* INSERM U602, Villejuif, France;
Université Paris-Sud, Institut André Lwoff, Villejuif, France;
Institute of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China; and
Institute for Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany
Several cytokines and growth factors are released by proteolytic cleavage of a membrane-anchored precursor, through the action of ADAM (a disintegrin and metalloprotease) metalloproteases. The activity of these proteases is regulated through largely unknown mechanisms. In this study we show that Ab engagement of several tetraspanins (CD9, CD81, CD82) increases epidermal growth factor and/or TNF-
secretion through a mechanism dependent on ADAM10. The effect of anti-tetraspanin mAb on TNF- release is rapid, not relayed by intercellular signaling, and depends on an intact MEK/Erk1/2 pathway. It is also associated with a concentration of ADAM10 in tetraspanin-containing patches. We also show that a large fraction of ADAM10 associates with several tetraspanins, indicating that ADAM10 is a component of the "tetraspanin web." These data show that tetraspanins regulate the activity of ADAM10 toward several substrates, and illustrate how membrane compartmentalization by tetraspanins can control the function of cell surface proteins such as ectoproteases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants from the Agence Nationale pour la Recherche, from the Groupement des Entreprises Françaises dans la Lutte contre le Cancer Paris Ile de France, the Association pour la Recherche contre le Cancer, and Nouvelles Recherches Biomédicales-Vaincre le Cancer. T.A. and C.A. were supported by fellowships awarded by the French government. T.A. and L.L. were recipients of a fellowship awarded by the Association Nouvelles Recherches Biomédicales. L.L. was also the recipient of a fellowship from the Fondation Franco-Chinoise pour la Science et ses Applications. A.L. is supported in part by the Interdisziplinäres Zentrum für Klinische Forschung Biomat, RWTH Aachen University, and by Sonderforschungsbereich 451, project A12 of the Deutsche Forschungsgemeinschaft.
2 E.R. and F.L.N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Eric Rubinstein, INSERM, U602, 14 Avenue Paul Vaillant Couturier, F-94807 Villejuif Cedex, France. E-mail address: eric.rubinstein{at}inserm.fr
4 Abbreviations used in this paper: ADAM, a disintegrin and metalloprotease; HB-EGF, heparin-binding epidermal growth factor; TPA, 12-O-tetradecanoyl-phorbol 13-acetate; MEF, mouse embryonic fibroblast; HEK, human embryonic kidney; siRNA, small interfering RNA; PKC, protein kinase C; GPCR, G protein-coupled receptor; HA, hemagglutinin.
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