ß-Arrestin 2 Mediates Endocytosis of Type III TGF-ß Receptor and Down-Regulation of Its Signaling

β-Arrestins bind to activated seven transmembrane–spanning (7TMS) receptors (G protein–coupled receptors) after the receptors are phosphorylated by G protein–coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of β-arrestin 2 (βarr2) for the single transmembrane–spanning type III transforming growth factor–β (TGF-β) receptor (TβRIII, also referred to as betaglycan). Binding of βarr2 to TβRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-β receptor (TβRII), which is itself a kinase, rather than by a GRK. Association with βarr2 led to internalization of both receptors and down-regulation of TGF-β signaling. Thus, the regulatory actions of β-arrestins are broader than previously appreciated, extending to the TGF-β receptor family as well.