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Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases.

The functions of beta-arrestin1 to facilitate clathrin-mediated endocytosis of the beta2-adrenergic receptor and to promote agonist-induced activation of extracellular signal-regulated kinases (ERK) are regulated by its phosphorylation/dephosphorylation at Ser-412. Cytoplasmic beta-arrestin1 is almost stoichiometrically phosphorylated at Ser-412. Dephosphorylation of beta-arrestin1 at the plasma membrane is required for targeting a signaling complex that includes the agonist-occupied receptors to the clathrin-coated pits. Here we demonstrate that beta-arrestin1 phosphorylation and function are modulated by an ERK-dependent negative feedback mechanism. ERK1 and ERK2 phosphorylate beta-arrestin1 at Ser-412 in vitro. Inhibition of ERK activity by a dominant-negative MEK1 mutant significantly attenuates beta-arrestin1 phosphorylation, thereby increasing the concentration of dephosphorylated beta-arrestin1. Under such conditions, beta-arrestin1-mediated beta2-adrenergic receptor internalization is enhanced as is its ability to bind clathrin. In contrast, if ERK-mediated phosphorylation is increased by transfection of a constitutively active MEK1 mutant, receptor internalization is inhibited. Our results suggest that dephosphorylated beta-arrestin1 mediates endocytosis-dependent ERK activation. Following activation, ERKs phosphorylate beta-arrestin1, thereby exerting an inhibitory feedback control of its function.

Pubmed ID: 10347142


  • Lin FT
  • Miller WE
  • Luttrell LM
  • Lefkowitz RJ


The Journal of biological chemistry

Publication Data

June 4, 1999

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL16037

Mesh Terms

  • Arrestins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line
  • Enzyme Activation
  • Enzyme Inhibitors
  • Feedback
  • Humans
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • Peptide Mapping
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Serine