Reciprocal Regulation of Angiotensin Receptor-activated Extracellular Signal-regulated Kinases by β-Arrestins 1 and 2

β-Arrestin2 not only plays essential roles in seven membrane-spanning receptor desensitization and internalization but also functions as a signal transducer in mitogen-activated protein kinase cascades. Here we show that the angiotensin II type 1A receptor-mediated activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HEK-293 cells is increased when the cellular level of β-arrestinl is down-regulated by RNA interference but is decreased or eliminated when the cellular level of β-arrestin2 is diminished. Such reciprocal effects of down-regulated levels of β-arrestins 1 and 2 are primarily due to differences in the ability of the two forms of β-arrestins to directly mediate ERK activation. These results are the first to demonstrate reciprocal activity of β-arrestin isoforms on a signaling pathway and suggest that physiological levels of β-arrestin1 may act as "dominant-negative" inhibitors of β -arrestin2-mediated ERK activation.