Rapid dephosphorylation of G protein-coupled receptors by protein phosphatase 1β is required for termination of β-arrestin-dependent signaling

J Biol Chem. 2011 Sep 23;286(38):32931-6. doi: 10.1074/jbc.M111.224899. Epub 2011 Jul 27.

Abstract

Termination of signaling of activated G protein-coupled receptors (GPCRs) is essential for maintenance of cellular homeostasis. It is well established that β-arrestin redistributes to phosphorylated GPCRs and thereby facilitates desensitization of classical G protein-dependent signaling. β-Arrestin in turn serves as a scaffold to initiate a second wave of signaling. Here, we report a molecular mechanism that regulates the termination of unconventional β-arrestin-dependent GPCR signaling. We identify protein phosphatase 1β (PP1β) as a phosphatase for the cluster of phosphorylated threonines ((353)TTETQRT(359)) within the sst(2A) somatostatin receptor carboxyl terminus that mediates β-arrestin binding using siRNA knock-down screening. We show that PP1β-mediated sst(2A) dephosphorylation is initiated directly after receptor activation at or near the plasma membrane. As a functional consequence of diminished PP1β activity, we find that somatostatin- and substance P-induced but not epidermal growth factor-induced ERK activation was aberrantly enhanced and prolonged. Thus, we demonstrate a novel mechanism for fine tuning unconventional β-arrestin-dependent GPCR signaling in that recruitment of PP1β to activated GPCRs facilitates GPCR dephosphorylation and, hence, leads to disruption of the β-arrestin-GPCR complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Arrestins / metabolism*
  • Biocatalysis / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HEK293 Cells
  • Humans
  • Marine Toxins
  • Molecular Sequence Data
  • Okadaic Acid / pharmacology
  • Oxazoles / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Protein Phosphatase 1 / metabolism*
  • Rats
  • Receptors, Somatostatin / chemistry
  • Receptors, Somatostatin / metabolism*
  • Serine / metabolism
  • Signal Transduction* / drug effects
  • Time Factors
  • beta-Arrestins

Substances

  • Arrestins
  • Marine Toxins
  • Oxazoles
  • Receptors, Somatostatin
  • beta-Arrestins
  • somatostatin receptor sst2A
  • Okadaic Acid
  • Serine
  • calyculin A
  • Extracellular Signal-Regulated MAP Kinases
  • PPP1CB protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1