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The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.

Publication ,  Journal Article
Tohgo, A; Choy, EW; Gesty-Palmer, D; Pierce, KL; Laporte, S; Oakley, RH; Caron, MG; Lefkowitz, RJ; Luttrell, LM
Published in: J Biol Chem
February 21, 2003

By binding to agonist-activated G protein-coupled receptors (GPCRs), beta-arrestins mediate homologous receptor desensitization and endocytosis via clathrin-coated pits. Recent data suggest that beta-arrestins also contribute to GPCR signaling by acting as scaffolds for components of the ERK mitogen-activated protein kinase cascade. Because of these dual functions, we hypothesized that the stability of the receptor-beta-arrestin interaction might affect the mechanism and functional consequences of GPCR-stimulated ERK activation. In transfected COS-7 cells, we found that angiotensin AT1a and vasopressin V2 receptors, which form stable receptor-beta-arrestin complexes, activated a beta-arrestin-bound pool of ERK2 more efficiently than alpha 1b and beta2 adrenergic receptors, which form transient receptor-beta-arrestin complexes. We next studied chimeric receptors in which the pattern of beta-arrestin binding was reversed by exchanging the C-terminal tails of the beta2 and V2 receptors. The ability of the V2 beta 2 and beta 2V2 chimeras to activate beta-arrestin-bound ERK2 corresponded to the pattern of beta-arrestin binding, suggesting that the stability of the receptor-beta-arrestin complex determined the mechanism of ERK2 activation. Analysis of covalently cross-linked detergent lysates and cellular fractionation revealed that wild type V2 receptors generated a larger pool of cytosolic phospho-ERK1/2 and less nuclear phospho-ERK1/2 than the chimeric V2 beta 2 receptor, consistent with the cytosolic retention of beta-arrestin-bound ERK. In stably transfected HEK-293 cells, the V2 beta 2 receptor increased ERK1/2-mediated, Elk-1-driven transcription of a luciferase reporter to a greater extent than the wild type V2 receptor. Furthermore, the V2 beta 2, but not the V2 receptor, was capable of eliciting a mitogenic response. These data suggest that the C-terminal tail of a GPCR, by determining the stability of the receptor-beta-arrestin complex, controls the extent of beta-arrestin-bound ERK activation, and influences both the subcellular localization of activated ERK and the physiologic consequences of ERK activation.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 21, 2003

Volume

278

Issue

8

Start / End Page

6258 / 6267

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Vasopressins
  • Transfection
  • Signal Transduction
  • Recombinant Proteins
  • Recombinant Fusion Proteins
  • Receptors, Cell Surface
  • Phosphorylation
  • Models, Biological
  • Mitogen-Activated Protein Kinases
 

Citation

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Tohgo, A., Choy, E. W., Gesty-Palmer, D., Pierce, K. L., Laporte, S., Oakley, R. H., … Luttrell, L. M. (2003). The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem, 278(8), 6258–6267. https://doi.org/10.1074/jbc.M212231200
Tohgo, Akira, Eric W. Choy, Diane Gesty-Palmer, Kristen L. Pierce, Stephane Laporte, Robert H. Oakley, Marc G. Caron, Robert J. Lefkowitz, and Louis M. Luttrell. “The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.J Biol Chem 278, no. 8 (February 21, 2003): 6258–67. https://doi.org/10.1074/jbc.M212231200.
Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, et al. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem. 2003 Feb 21;278(8):6258–67.
Tohgo, Akira, et al. “The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.J Biol Chem, vol. 278, no. 8, Feb. 2003, pp. 6258–67. Pubmed, doi:10.1074/jbc.M212231200.
Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, Caron MG, Lefkowitz RJ, Luttrell LM. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem. 2003 Feb 21;278(8):6258–6267.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 21, 2003

Volume

278

Issue

8

Start / End Page

6258 / 6267

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Vasopressins
  • Transfection
  • Signal Transduction
  • Recombinant Proteins
  • Recombinant Fusion Proteins
  • Receptors, Cell Surface
  • Phosphorylation
  • Models, Biological
  • Mitogen-Activated Protein Kinases