βarrestin2 interacts with TβRII to regulate Smad-dependent and Smad-independent signal transduction

The Transforming Growth Factor beta (TGF beta) signaling pathway is necessary for a variety of normal cellular processes. However, the distinct mechanisms involved in TGF beta receptor turnover and the effect on signal transduction have yet to be fully elucidated. We have previously shown that T beta RIII is able to interact with the T beta RII/T beta RI complex to increase clathrin-dependent endocytosis and receptor half-life. Others have shown that beta arrestin2 binds T beta RIII to mediate T beta RII/T beta RIII endocytosis. To further understand the mechanism regulating TGF beta receptor signaling, we evaluated the role of beta arrestin2 in TGF beta receptor signal transduction, half-life and trafficking. We have found that T beta RII binds beta arrestin2 in the absence of T beta RIII. Furthermore, using immunofluorescence microscopy we show that beta arrestin2 traffics to the early endosome with T beta RII. We investigated the effect of loss of beta arrestin2 on T beta RII dynamics and found that loss of beta arrestin2 increases steady-state levels of T beta RII at the cell surface. The interaction of T beta RII with beta arrestin2 is involved in modulating TGF beta signal transduction, as loss of beta arrestin2 increases the phosphorylation of p38 and modestly affects pSmad levels. Using a luciferase assay to assess TGF beta-dependent transcription we show that loss of beta arrestin2 decreases Smad-dependent TGF beta-stimulated transcription. Furthermore, loss of beta arrestin2 increases p38 signal transduction, which correlated with increased cell death via apoptosis. Overall, our results suggest a role for beta arrestin2 in the regulation of Smad-dependent and independent TGF beta pathways. (C) 2012 Elsevier Inc. All rights reserved.