The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptor

Abstract

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

PICK1 promotes caveolin-dependent degradation of TGF-β type I receptor

“…npg TGF-β receptors are dynamically distributed on the plasma membrane [10]. Interleukin-6 [43], ADAM12 [44] and cholesterol depletion [45] can partition TβRI from the lipid raft microdomains into non-lipid raft regions, while hyaluronan [46] and the polysaccharide heparin sulfate [47] promote lipid raft localization of TβRI. Several lines of evidence showed that caveolin, which is enriched in lipid rafts, is required for TβRI turnover [38,46,48,49].…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…In activated hepatic stellate cells, TGF-βl induces ADAM-12 expression which might also participate in tumour progression [139]. It is worth pointing out that a recent study identified ADAM-12 as a partner of TGFβ receptor II signalling where it stabilizes the TGFβ RII protein and potentiates Smad-mediated signalling [140]. Hence, ADAM-12 might contribute to growth inhibitory signalling in normal epithelial cells which is lost during tumour progression.…”

Endocytic regulation of TGF-β signaling

“…ADAM12 (a disintegrin and metalloproteinase 12) is a glycoprotein with zinc protease and integrin-binding activities in its extracellular domain and has been implicated in the control of membrane fusion, cytokine and growth factor shedding, and cell migration [98]. A recent study reported that it can interact with the extracellular domain of TbRII and enhance TGF-b signaling [99]. Interestingly, neither its protease activity nor the intracellular domain is required for this stimulatory effect.…”