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Published online July 9, 2007
doi:10.1083/jcb.200612046
The Journal of Cell Biology, Vol. 178, No. 2, 201-208
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Atfi et al.
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 The disintegrin and metalloproteinase ADAM12 contributes to TGF-ß signaling through interaction with the type II receptor

Azeddine Atfi1, Emmanuelle Dumont2, Frédéric Colland3, Dominique Bonnier2, Annie L'Helgoualc'h2, Céline Prunier1, Nathalie Ferrand1, Bruno Clément2, Ulla M. Wewer4, and Nathalie Théret2

1 Institut National de la Santé et de la Recherche Medicale, Unite 673, Hôpital St-Antoine, 75571 Paris, France
2 Institut National de la Santé et de la Recherche Medicale, Unite 620, Institut Federatif de Recherche 140, Université de Rennes I, 35043 Rennes, France
3 Hybrigenics, 75014 Paris, France
4 Department of Biomedicine and Biotech Research and Innovation Centre, University of Copenhagen, DK-1017 Copenhagen, Denmark

Correspondence to Nathalie Théret: nathalie.theret{at}univ-rennes1.fr

Transforming growth factor-ß (TGF-ß) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-ß type I receptor and the TGF-ß type II receptor (TßRII). Upon ligand binding, TGF-ß type I receptor activated by TßRII propagates signals to Smad proteins, which mediate the activation of TGF-ß target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-ß signaling pathway that acts through association with TßRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-ß signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TßRII in early endosomal vesicles and stabilizes the TßRII protein presumably by suppressing the association of TßRII with Smad7. These results define ADAM12 as a new partner of TßRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.

Abbreviations used in this paper: ADAM, a disintegrin and metalloproteinase; EEA1, early endosomal antigen 1; HSC, hepatic stellate cell; PAI-1, plasminogen activator inhibitor-1; RD, Rhabdomyosarcoma; SARA, Smad anchor for receptor activation; shRNA, short hairpin RNA; TßRII, TGF-ß type II receptor.


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