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Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.

Publication ,  Journal Article
Kim, I-M; Tilley, DG; Chen, J; Salazar, NC; Whalen, EJ; Violin, JD; Rockman, HA
Published in: Proc Natl Acad Sci U S A
September 23, 2008

Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (beta(1)AR) to transactivate the EGFR. To determine whether beta-adrenergic ligands that do not activate G protein signaling (i.e., beta-blockers) can stabilize the beta(1)AR in a signaling conformation, we screened 20 beta-blockers for their ability to stimulate beta-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce beta(1)AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the beta(1)AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against beta-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires beta(1)AR phosphorylation at consensus G protein-coupled receptor kinase sites and beta-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, beta-arrestin-dependent fashion.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 23, 2008

Volume

105

Issue

38

Start / End Page

14555 / 14560

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transcriptional Activation
  • Signal Transduction
  • Quinazolines
  • Propanolamines
  • Phosphorylation
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Kim, I.-M., Tilley, D. G., Chen, J., Salazar, N. C., Whalen, E. J., Violin, J. D., & Rockman, H. A. (2008). Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A, 105(38), 14555–14560. https://doi.org/10.1073/pnas.0804745105
Kim, Il-Man, Douglas G. Tilley, Juhsien Chen, Natasha C. Salazar, Erin J. Whalen, Jonathan D. Violin, and Howard A. Rockman. “Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.Proc Natl Acad Sci U S A 105, no. 38 (September 23, 2008): 14555–60. https://doi.org/10.1073/pnas.0804745105.
Kim I-M, Tilley DG, Chen J, Salazar NC, Whalen EJ, Violin JD, et al. Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555–60.
Kim, Il-Man, et al. “Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.Proc Natl Acad Sci U S A, vol. 105, no. 38, Sept. 2008, pp. 14555–60. Pubmed, doi:10.1073/pnas.0804745105.
Kim I-M, Tilley DG, Chen J, Salazar NC, Whalen EJ, Violin JD, Rockman HA. Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555–14560.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 23, 2008

Volume

105

Issue

38

Start / End Page

14555 / 14560

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transcriptional Activation
  • Signal Transduction
  • Quinazolines
  • Propanolamines
  • Phosphorylation
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice, Inbred C57BL
  • Mice