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Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2.

Publication ,  Journal Article
Wei, H; Ahn, S; Barnes, WG; Lefkowitz, RJ
Published in: J Biol Chem
November 12, 2004

Binding of beta-arrestins to seven-membrane-spanning receptors (7MSRs) not only leads to receptor desensitization and endocytosis but also elicits additional signaling processes. We recently proposed that stimulation of the angiotensin type 1A (AT(1A)) receptor results in independent beta-arrestin 2- and G protein-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation. Here we utilize two AT(1A) mutant receptors to study these independent pathways, one truncated at residue 324, thus removing all potential carboxyl-terminal phosphorylation sites, and the other bearing four mutations in the serine/threonine-rich clusters in the carboxyl terminus. As assessed by confocal microscopy, the two mutant receptors interacted with beta-arrestin 2-green fluorescent protein with much lower affinity than did the wild-type receptor. In addition, the mutant receptors more robustly stimulated G protein-mediated inositol phosphate production. Approximately one-half of the wild-type AT(1A) receptor-stimulated ERK1/2 activation was via a beta-arrestin 2-dependent pathway (suppressed by beta-arrestin 2 small interfering RNA), whereas the rest was mediated by a G protein-dependent pathway (suppressed by protein kinase C inhibitor). ERK1/2 activation by the mutant receptors was insensitive to beta-arrestin 2 small interfering RNA but was reduced more than 80% by a protein kinase C inhibitor. The biochemical consequences of ERK activation by the G protein and beta-arrestin 2-dependent pathways were also distinct. G-protein-mediated ERK activation enhanced the transcription of early growth response 1, whereas beta-arrestin 2-dependent ERK activation did not. In addition, stimulation of the truncated AT(1A) mutant receptor caused significantly greater early growth response 1 transcription than did the wild-type receptor. These findings demonstrate how the ability of receptors to interact with beta-arrestins determines both the mechanism of ERK activation as well as the physiological consequences of this activation.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 12, 2004

Volume

279

Issue

46

Start / End Page

48255 / 48261

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Transcription Factors
  • Sequence Alignment
  • Second Messenger Systems
  • Recombinant Fusion Proteins
  • Receptor, Angiotensin, Type 1
  • RNA, Small Interfering
  • Protein Kinase C
  • Protein Binding
 

Citation

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Wei, H., Ahn, S., Barnes, W. G., & Lefkowitz, R. J. (2004). Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2. J Biol Chem, 279(46), 48255–48261. https://doi.org/10.1074/jbc.M406205200
Wei, Huijun, Seungkirl Ahn, William G. Barnes, and Robert J. Lefkowitz. “Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2.J Biol Chem 279, no. 46 (November 12, 2004): 48255–61. https://doi.org/10.1074/jbc.M406205200.
Wei, Huijun, et al. “Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2.J Biol Chem, vol. 279, no. 46, Nov. 2004, pp. 48255–61. Pubmed, doi:10.1074/jbc.M406205200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 12, 2004

Volume

279

Issue

46

Start / End Page

48255 / 48261

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Transcription Factors
  • Sequence Alignment
  • Second Messenger Systems
  • Recombinant Fusion Proteins
  • Receptor, Angiotensin, Type 1
  • RNA, Small Interfering
  • Protein Kinase C
  • Protein Binding