β-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation

Abstract

␤-Arrestins, originally discovered as terminators of G protein-coupled receptor signaling, have more recently been appreciated to also function as signal transducers in their own right, although the consequences for cellular physiology have not been well understood. Here we demonstrate that ␤-arrestin-2 mediates anti-apoptotic cytoprotective signaling stimulated by a typical 7-transmembrane receptor the angiotensin ATII 1A receptor, expressed endogenously in rat vascular smooth muscle cells or by transfection in HEK-293 cells. Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. Anti-apoptotic effects as well as pathway activities can be stimulated by an angiotensin analog (SII), which has been previously shown to activate ␤-arrestin but not G protein-dependent signaling, and are abrogated by ␤-arrestin-2 small interfering RNA. These findings establish a key role for ␤-arrestin-2 in mediating cellular cytoprotective functions by a 7-transmembrane receptor and define the biochemical pathways involved.

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

“…However, SII-mediated ERK phosphorylation is graded and slow with localization of phosphorylated ERK (pERK) in the cytoplasm (11). AngII activates apoptotic signals while SII activates anti-apoptotic ones (12). Great efforts have been made to identify unique signaling pathways of -arrestin-biased agonists.…”

Biased Agonism of the Angiotensin II Type I Receptor

“…12,13) Ex vivo studies further revealed that SII treatment had positive inotropic and lusitropic effects in cardiomyocytes isolated from wildtype mice but not in cardiomyocytes from β-arrestin2 deficient mice. 14) Consistent with the previous in vitro studies, SII was able to activate MAPK in perfused hearts.…”

“…13) To examine whether AT1R-β-arrestin signaling triggered by mechanical stretch acts as a prosurvival signal, hearts isolated from wild-type mice, AT1aR-deficient mice and β-arrestin2-deficient mice were subjected to balloon stretch ex vivo. Mechanical stretch resulted in Akt phosphorylation in wild-type hearts but not in AT1aR-deficient hearts or in β-arrestin2-deficient hearts.…”

G Protein-Coupled Receptor Dependent NF-κB Signaling in Atherogenesis

“…Intriguingly, recent studies demonstrate that in VSMCs, arrestin 2 mediates AGTR1-dependent prevention of apoptosis and is required for both LPA and thrombin-induced vascular smooth muscle cell proliferation (Ahn et al, 2009;Kim et al, 2008). Furthermore, deficiency of arrestin 2 protects LDL receptor knockout (ldlr -/-) mice from aortic atherosclerosis (Kim et al, 2008).…”