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

Abstract

beta-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 beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII 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-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.

Signaling Receptors for TGF-β Family Members

“…Akt is activated by PI3-kinase (e.g., downstream of tyrosine kinase receptors), such as the insulin receptor; thus, activation of such receptors makes cells more susceptible to TGF-b stimulation. TbRII phosphorylates the carboxyl tail of betaglycan, which promotes clathrin-dependent endocytosis of the TGF-b receptor complex (Chen et al 2003). TbRII also binds the retromer vacuolar protein-sorting protein 26 (Vps26) in a TGF-b-independent manner; this interaction was found to be of crucial importance for proper receptor recycling and for insertion of the receptor on the basolateral side of polarized MDCK epithelial cells (Yin et al 2013).…”

“…Clathrin-independent internalization of betaglycan seems to be required for efficient activation of both Smad2 and p38 MAP kinase phosphorylation. Phosphorylation of betaglycan on Thr841 by TbRII promotes the association of the scaffolding protein b-arrestin, which mediates interaction with flottilin of lipid rafts and promotes endocytosis of betaglycan (Chen et al 2003). TbRII was found to bind the transmembrane metalloproteinase ADAM12, which, in a protease-independent manner, promotes sorting of TbRII to early endosomes, competes with its binding to Smad7, and thereby prevents its degradation (Atfi et al 2007).…”

Endocytic regulation of TGF-β signaling

“…b-Arrestin 2 can bind to the type III TGF-b receptor betaglycan, and this binding is triggered by TbRII-mediated phosphorylation on the intracellular domain of betaglycan [112]. More importantly, the association of betaglycan with b-arrestin 2 leads to the internalization of both TbRII and betaglycan and thus downregulation of TGF-b signaling.…”

A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor-β Receptor Controls Basolateral Delivery

“…Three mammalian TGF␤ isoforms have been described to date, termed TGF␤-1, -2, and -3, which generally exhibit similar overall effects in vitro, yet they have distinct activities in vivo (Hartsough and Mulder, 1997;Kulkarni et al, 2002). They signal through three distinct mammalian TGF␤ binding transmembrane proteins, termed type I, type II, and type III receptors (Laiho et al, 1990(Laiho et al, , 1991Lopez-Casillas et al, 1991;Wang et al, 1991;Chen et al, 2003). The type I and type II TGF␤ receptors are single-pass, transmembrane serine/threonine kinases of 53 and 75 kDa, respectively (Lin et al, 1992;Bassing et al, 1994).…”