Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.
beta-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 beta-arrestin1 is down-regulated by RNA interference but is decreased or eliminated when the cellular level of beta-arrestin2 is diminished. Such reciprocal effects of down-regulated levels of beta-arrestins 1 and 2 are primarily due to differences in the ability of the two forms of beta-arrestins to directly mediate ERK activation. These results are the first to demonstrate reciprocal activity of beta-arrestin isoforms on a signaling pathway and suggest that physiological levels of beta-arrestin1 may act as "dominant-negative" inhibitors of beta-arrestin2-mediated ERK activation.
Ahn
Seungkirl
S
Howard Hughes Medical Institute, Department of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
Wei
Huijun
H
Garrison
Tiffany Runyan
TR
Lefkowitz
Robert J
RJ
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000071557:beta-Arrestins
D019390:Arrestins; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases