The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor.
Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the TbetaRII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.
Atfi
Azeddine
A
Institut National de la Santé et de la Recherche Medicale, Unite 673, Hôpital St-Antoine, Paris, France.
Dumont
Emmanuelle
E
Colland
Frédéric
F
Bonnier
Dominique
D
L'helgoualc'h
Annie
A
Prunier
Céline
C
Ferrand
Nathalie
N
Clément
Bruno
B
Wewer
Ulla M
UM
Théret
Nathalie
N
D051722:ADAM Proteins / Q000378:metabolism*; D000072199:ADAM12 Protein; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008907:Mink; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D010957:Plasmids; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta; D020798:Two-Hybrid System Techniques
D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D008156:Luciferases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; C096115:Adam12 protein, mouse