The disintegrin and metalloproteinase ADAM12 contributes to TGF-β 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 11 receptor (T beta RII). Upon ligand binding, TGF-beta type I receptor activated by T beta RII 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 T beta RII. 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 T beta RII in early endosomal vesicles and stabilizes the T beta RII protein presumably by suppressing the association of T beta RII with Smad7. These results define ADAM12 as a new partner of T beta RII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.