ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin

Abstract

The activity of a variety of extracellular signaling factors is tightly regulated by proteins containing A Disintegrin And a Metalloprotease domain (ADAM) metalloproteases through limited proteolysis. Thus, the identification of ADAM substrates may unveil novel components and mechanisms of cell signaling pathways. We report the identification of the transmembrane protein vasorin (VASN), a transforming growth factor-b (TGFb) trap, as a substrate of ADAM17. The metalloprotease efficiently generates a soluble fragment encompassing the extracellular domain of VASN. Despite the importance of TGFb in normal development and tumor progression, the regulation of VASN is completely unknown. Here, we show that only the soluble form of VASN inhibits TGFb and that the secretion of VASN is tightly controlled by ADAM17. Hence, inhibition of ADAM17 leads to the upregulation of TGFb signaling. Adding a new level of complexity to the function of ADAM17, we finally show that, through the cleavage of VASN, the metalloprotease controls TGFb-mediated epithelial-to-mesenchymal transition.

The Presence of the Y-Chromosome, Not the Absence of the Second X-Chromosome, Alters the mRNA Levels Stored in the Fully Grown XY Mouse Oocyte

“…Agtr1a , Epas1 , and Vasn are known to play roles in ovulation [48], [49], [50], [51], [52]. We have previously reported that follicular development is largely normal up to the antral stage but rarely reaches the preovulatory stage in the XY ovary [40], and very few or no oocytes are ovulated by XY females by gonadotropin treatment [53].…”

ADAM17: a molecular switch to control inflammation and tissue regeneration

“…Stimulation of T cells with TGFb in the presence of IL-6 and sIL-6R led to more suppression of Treg cell differentiation than in the presence of IL-6 alone, indicating that IL-6 trans-signaling contributes to regulate the balance between Treg cells and Th17 cells [26]. The involvement of ADAM17 in this balance is further supported by the fact that TGFb activity is regulated by cleavage of vasorin, a protein that binds and neutralizes TGFb in its soluble but not in its cellbound form, thereby influencing the generation of regulatory T cells by TGFb [27]. These data show that ADAM17 activity influences various aspects of T cell biology.…”

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

“…Limited proteolysis by ADAM17 generates a soluble fragment encompassing the extracellular VASN domain, which directly binds to transforming growth factor (TGF)β and attenuates TGFβ signaling [100]. As in the case of ADAM10, ADAM17-dependent shedding has been demonstrated to be stimulated by thrombin [101].…”