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

J Biol Chem. 2002 Mar 15;277(11):9429-36. doi: 10.1074/jbc.M106457200. Epub 2002 Jan 2.


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.

MeSH terms

  • Animals
  • Arrestins / physiology*
  • COS Cells
  • Cytosol / enzymology*
  • GTP-Binding Proteins / physiology
  • Hydrolysis
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylinositols / metabolism
  • Phosphorylation
  • Proteins / physiology
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / drug effects
  • Receptors, Angiotensin / physiology*
  • Receptors, Cell Surface / physiology
  • TNF Receptor-Associated Factor 3
  • Transcription, Genetic*
  • beta-Arrestins


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