Feedback Regulation of β-Arrestin1 Function by Extracellular Signal-regulated Kinases*

  1. Robert J. Lefkowitz
  1. From the Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

Abstract

The functions of β-arrestin1 to facilitate clathrin-mediated endocytosis of the β2-adrenergic receptor and to promote agonist-induced activation of extracellular signal-regulated kinases (ERK) are regulated by its phosphorylation/dephosphorylation at Ser-412. Cytoplasmic β-arrestin1 is almost stoichiometrically phosphorylated at Ser-412. Dephosphorylation of β-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 β-arrestin1 phosphorylation and function are modulated by an ERK-dependent negative back mechanism. ERK1 and ERK2 phosphorylate β-arrestin1 at Ser-412 in vitro. Inhibition of ERK activity by a dominant-negative MEK1 mutant significantly attenuates β-arrestin1 phosphorylation, thereby increasing the concentration of dephosphorylated β-arrestin1. Under such conditions, β-arrestin1-mediated β2-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 β-arrestin1 mediates endocytosis-dependent ERK activation. Following activation, ERKs phosphorylate β-arrestin1, thereby exerting an inhibitory back control of its function.

Footnotes

  • * This work was supported by the Howard Hughes Medical Institute and by Grant HL16037 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Inst., Dept. of Medicine and Biochemistry, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail: lefko001{at}mc.duke.edu.

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    ERK
    extracellular signal-regulated kinase(s)
    PAGE
    polyacrylamide gel electrophoresis
    • Received March 19, 1999.
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