CD109‐mediated degradation of TGF‐β receptors and inhibition of TGF‐β responses involve regulation of SMAD7 and Smurf2 localization and function

Transforming growth factor‐β (TGF‐β) is a multifunctional cytokine that regulates a wide variety of cellular processes including proliferation, differentiation, and extracellular matrix deposition. Dysregulation of TGF‐β signaling is associated with several diseases such as cancer and tissue fibrosis. TGF‐β signals through two transmembrane proteins known as the type I (TGFBR1) and type II (TGFBR2) receptors. The levels of these receptors at the cell surface are tightly regulated by several mechanisms, including degradation following recruitment of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor (Smurf) 2 by SMAD7. In addition, TGF‐β co‐receptors can modulate TGF‐β signaling receptor activity in a cell‐specific manner. We have previously identified a novel TGF‐β co‐receptor, CD109, a glycosyl phosphatidylinositol (GPI)‐anchored protein that negatively regulates TGF‐β signaling. Despite CD109's potential relevance as a regulator of TGF‐β action in vivo, the mechanisms by which CD109 regulates TGF‐β signaling are still incompletely understood. Previously, we have shown that CD109 downregulates TGF‐β signaling by promoting TGF‐β receptor localization into the lipid raft/caveolae compartment and by enhancing TGF‐β receptor degradation. Here, we demonstrate that CD109 enhances SMAD7/Smurf2‐mediated degradation of TGFBR1 in a ligand‐dependent manner. Moreover, we show that CD109 regulates the localization and the association of SMAD7/Smurf2 with TGFBR1. Finally, we demonstrate that CD109's inhibitory effect on TGF‐β signaling and responses require SMAD7 expression and Smurf2 ubiquitin ligase activity. Taken together, these results suggest that CD109 is an important regulator of SMAD7/Smurf2‐mediated degradation of TGFBR1. J. Cell. Biochem. 113: 238–246, 2012. © 2011 Wiley Periodicals, Inc.