title: Arrestin-dependent angiotensin AT1 receptor signaling regulates Akt and mTor-mediated protein synthesis.
abstract: Control of protein synthesis is critical to both cell growth and proliferation. The mammalian target of rapamycin (mTOR) integrates upstream growth, proliferation, and survival signals, including those transmitted via ERK1/2 and Akt, to regulate the rate of protein translation. The angiotensin AT1 receptor has been shown to activate both ERK1/2 and Akt in arrestin-based signalsomes. Here, we examine the role of arrestin-dependent regulation of ERK1/2 and Akt in the stimulation of mTOR-dependent protein translation by the AT1 receptor using HEK293 and primary vascular smooth muscle cell models. Nascent protein synthesis stimulated by both the canonical AT1 receptor agonist angiotensin II (AngII), and the arrestin pathway-selective agonist [Sar(1)-Ile(4)-Ile(8)]AngII (SII), is blocked by shRNA silencing of βarrestin1/2 or pharmacological inhibition of Akt, ERK1/2, or mTORC1. In HEK293 cells, SII activates a discrete arrestin-bound pool of Akt and promotes Akt-dependent phosphorylation of mTOR and its downstream effector p70/p85 ribosomal S6 kinase (p70/85S6K). In parallel, SII-activated ERK1/2 helps promote mTOR and p70/85S6K phosphorylation, and is required for phosphorylation of the known ERK1/2 substrate p90 ribosomal S6 kinase (p90RSK). Thus, arrestins coordinate AT1 receptor regulation of ERK1/2 and Akt activity and stimulate protein translation via both Akt-mTOR-p70/85S6K and ERK1/2-p90RSK pathways. These results suggest that in vivo, arrestin pathway-selective AT1 receptor agonists may promote cell growth or hypertrophy through arrestin-mediated mechanisms despite their antagonism of G protein signaling.
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Ryan T
authors: RT
authors: Kendall
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Mi-Hye
authors: MH
authors: Lee
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Dorea L
authors: DL
authors: Pleasant
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Katherine
authors: K
authors: Robinson
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401.
authors: Dhandapani
authors: D
authors: Kuppuswamy
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401.
authors: Paul J
authors: PJ
authors: McDermott
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401. Electronic address: luttrell@musc.edu.
authors: Louis M
authors: LM
authors: Luttrell
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D046912:Multiprotein Complexes; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D000804:Angiotensin II; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Akt PKB; Angiotensin II; Arrestin; Biased Agonism; G Protein-coupled Receptor (GPCR); Mammalian Target of Rapamycin (mTOR); Vascular Smooth Muscle Cells