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Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.

Publication ,  Journal Article
Luttrell, LM; Roudabush, FL; Choy, EW; Miller, WE; Field, ME; Pierce, KL; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
February 27, 2001

Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of beta-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a receptors (AT1aR). In HEK-293 cells expressing hemagglutinin-tagged AT1aR, angiotensin stimulation triggered beta-arrestin-2 binding to the receptor and internalization of AT1aR-beta-arrestin complexes. Using red fluorescent protein-tagged ERK2 to track the subcellular distribution of ERK2, we found that angiotensin treatment caused the redistribution of activated ERK2 into endosomal vesicles that also contained AT1aR-beta-arrestin complexes. This targeting of ERK2 reflects the formation of multiprotein complexes containing AT1aR, beta-arrestin-2, and the component kinases of the ERK cascade, cRaf-1, MEK1, and ERK2. Myc-tagged cRaf-1, MEK1, and green fluorescent protein-tagged ERK2 coprecipitated with Flag-tagged beta-arrestin-2 from transfected COS-7 cells. Coprecipitation of cRaf-1 with beta-arrestin-2 was independent of MEK1 and ERK2, whereas the coprecipitation of MEK1 and ERK2 with beta-arrestin-2 was significantly enhanced in the presence of overexpressed cRaf-1, suggesting that binding of cRaf-1 to beta-arrestin facilitates the assembly of a cRaf-1, MEK1, ERK2 complex. The phosphorylation of ERK2 in beta-arrestin complexes was markedly enhanced by coexpression of cRaf-1, and this effect is blocked by expression of a catalytically inactive dominant inhibitory mutant of MEK1. Stimulation with angiotensin increased the binding of both cRaf-1 and ERK2 to beta-arrestin-2, and the association of beta-arrestin-2, cRaf-1, and ERK2 with AT1aR. These data suggest that beta-arrestins function both as scaffolds to enhance cRaf-1 and MEK-dependent activation of ERK2, and as targeting proteins that direct activated ERK to specific subcellular locations.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 27, 2001

Volume

98

Issue

5

Start / End Page

2449 / 2454

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Mitogen-Activated Protein Kinase 1
  • Microscopy, Confocal
  • Humans
  • Enzyme Activation
  • Cell Line
  • Arrestins
  • Animals
  • Angiotensin II
 

Citation

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Luttrell, L. M., Roudabush, F. L., Choy, E. W., Miller, W. E., Field, M. E., Pierce, K. L., & Lefkowitz, R. J. (2001). Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A, 98(5), 2449–2454. https://doi.org/10.1073/pnas.041604898
Luttrell, L. M., F. L. Roudabush, E. W. Choy, W. E. Miller, M. E. Field, K. L. Pierce, and R. J. Lefkowitz. “Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.Proc Natl Acad Sci U S A 98, no. 5 (February 27, 2001): 2449–54. https://doi.org/10.1073/pnas.041604898.
Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449–54.
Luttrell, L. M., et al. “Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.Proc Natl Acad Sci U S A, vol. 98, no. 5, Feb. 2001, pp. 2449–54. Pubmed, doi:10.1073/pnas.041604898.
Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449–2454.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 27, 2001

Volume

98

Issue

5

Start / End Page

2449 / 2454

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Mitogen-Activated Protein Kinase 1
  • Microscopy, Confocal
  • Humans
  • Enzyme Activation
  • Cell Line
  • Arrestins
  • Animals
  • Angiotensin II