The TGF-β co-receptor, CD109, promotes internalization and degradation of TGF-β receptors

Abstract

Transforming growth factor-β (TGF-β) is implicated in numerous pathological disorders, including cancer and mediates a broad range of biological responses by signaling through the type I and II TGF-β receptors. Internalization of these receptors via the clathrin-coated pits pathway facilitates SMAD-mediated signaling, whereas internalization via the caveolae pathway is associated with receptor degradation. Thus, molecules that modulate receptor endocytosis are likely to play a critical role in regulating TGF-β action. We previously identified CD109, a GPI-anchored protein, as a TGF-β co-receptor and a negative regulator of TGF-β signaling. Here, we demonstrate that CD109 associates with caveolin-1, a major component of the caveolae. Moreover, CD109 increases binding of TGF-β to its receptors and enhances their internalization via the caveolae. In addition, CD109 promotes localization of the TGF-β receptors into the caveolar compartment in the presence of ligand and facilitates TGF-β-receptor degradation. Thus, CD109 regulates TGF-β receptor endocytosis and degradation to inhibit TGF-β signaling. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

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

“…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]. In the current study, we found that PICK1 could promote caveolae localization of TβRI.…”

Signaling Receptors for TGF-β Family Members

“…It also forms a complex with TGF-b signaling receptors and negatively regulates TGF-b signaling (Finnson et al 2006). CD109 directs the localization of TGF-b receptors to caveolae and promotes their degradation (Bizet et al 2011) in a process involving Smad7 and Smurf2 (Bizet et al 2012). …”

Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing

“…17 On the other hand, there are some factors, such as CD109, that function as coreceptors for TGF-b. 18 It has been shown that CD109, which is a 180 kDa glycosylphosphatidylinositol-anchored protein, serves as an inhibitor of TGF-b signaling in human keratinocytes. 19 The role of TGF-b1 during the wound healing process.…”