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beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.

Publication ,  Journal Article
Tohgo, A; Pierce, KL; Choy, EW; Lefkowitz, RJ; Luttrell, LM
Published in: J Biol Chem
March 15, 2002

beta-Arrestins are cytosolic proteins that mediate homologous desensitization of G protein-coupled receptors (GPCRs) by binding to agonist-occupied receptors and by uncoupling them from heterotrimeric G proteins. The recent finding that beta-arrestins bind to some mitogen-activated protein (MAP) kinases has suggested that they might also function as scaffolds for GPCR-stimulated MAP kinase activation. To define the role of beta-arrestins in the regulation of ERK MAP kinases, we examined the effect of beta-arrestin overexpression on ERK1/2 activation and nuclear signaling in COS-7 cells expressing angiotensin II type 1a receptors (AT1aRs). Expression of either beta-arrestin1 or beta-arrestin2 reduced angiotensin-stimulated phosphatidylinositol hydrolysis but paradoxically increased angiotensin-stimulated ERK1/2 phosphorylation. The increase in ERK1/2 phosphorylation in beta-arrestin-expressing cells correlated with activation of a beta-arrestin-bound pool of ERK2. The beta-arrestin-dependent increase in ERK1/2 phosphorylation was accompanied by a significant reduction in ERK1/2-mediated, Elk1-driven transcription of a luciferase reporter. Analysis of the cellular distribution of phospho-ERK1/2 by confocal immunofluorescence microscopy and cellular fractionation revealed that overexpression of beta-arrestin resulted in a significant increase in the cytosolic pool of phospho-ERK1/2 and a corresponding decrease in the nuclear pool of phospho-ERK1/2 following angiotensin stimulation. beta-Arrestin overexpression resulted in formation of a cytoplasmic pool of beta-arrestin-bound phospho-ERK, decreased nuclear translocation of phospho-ERK1/2, and inhibition of Elk1-driven luciferase transcription even when ERK1/2 was activated by overexpression of cRaf-1 in the absence of AT1aR stimulation. These data demonstrate that beta-arrestins facilitate GPCR-mediated ERK activation but inhibit ERK-dependent transcription by binding to phospho-ERK1/2, leading to its retention in the cytosol.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

March 15, 2002

Volume

277

Issue

11

Start / End Page

9429 / 9436

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transcription, Genetic
  • TNF Receptor-Associated Factor 3
  • Receptors, Cell Surface
  • Receptors, Angiotensin
  • Receptor, Angiotensin, Type 1
  • Proteins
  • Phosphorylation
  • Phosphatidylinositols
  • Mitogen-Activated Protein Kinases
 

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Tohgo, A., Pierce, K. L., Choy, E. W., Lefkowitz, R. J., & Luttrell, L. M. (2002). beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation. J Biol Chem, 277(11), 9429–9436. https://doi.org/10.1074/jbc.M106457200
Tohgo, Akira, Kristen L. Pierce, Eric W. Choy, Robert J. Lefkowitz, and Louis M. Luttrell. “beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.J Biol Chem 277, no. 11 (March 15, 2002): 9429–36. https://doi.org/10.1074/jbc.M106457200.
Tohgo, Akira, et al. “beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.J Biol Chem, vol. 277, no. 11, Mar. 2002, pp. 9429–36. Pubmed, doi:10.1074/jbc.M106457200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

March 15, 2002

Volume

277

Issue

11

Start / End Page

9429 / 9436

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transcription, Genetic
  • TNF Receptor-Associated Factor 3
  • Receptors, Cell Surface
  • Receptors, Angiotensin
  • Receptor, Angiotensin, Type 1
  • Proteins
  • Phosphorylation
  • Phosphatidylinositols
  • Mitogen-Activated Protein Kinases