The role of beta-arrestins in the formyl peptide receptor-like 1 internalization and signaling

Cell Signal. 2007 Sep;19(9):1939-48. doi: 10.1016/j.cellsig.2007.05.006. Epub 2007 May 29.

Abstract

The N-formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor (GPCR) that transmits intracellular signals in response to a variety of agonists, many of them being clearly implicated in human pathology. beta-arrestins are adaptor proteins that uncouple GPCRs from G protein and regulate receptor internalization. They can also function as signal transducers through the scaffolding of signaling molecules, such as components of the extracellular signal-regulated kinase (ERK) cascade. We investigated the role of beta-arrestins in ligand-induced FPRL1 internalization and signaling. In HEK293 cells expressing FPRL1, fluorescence microscopy revealed that agonist-stimulated FPRL1 remained co-localized with beta-arrestins during endocytosis. Internalization of FPRL1, expressed in a mouse embryonic fibroblast (MEF) cell line lacking endogenous beta-arrestins, was highly compromised. This distinguishes FPRL1 from the prototypical formyl peptide receptor FPR that is efficiently internalized in the absence of beta-arrestins. In both HEK293 and MEF cells, FPRL1-mediated ERK1/2 activation was a rapid and transient event. The kinetics and extent of ERK1/2 activation were not significantly modified by beta-arrestin overexpression. The pattern of FPRL1-mediated ERK1/2 activation was similar whether cells express or not beta-arrestins. Furthermore, treatment of the FPRL1 expressing cells with pertussis toxin inhibited ERK1/2 activation in MEF and in HEK293 cells. These results led us to conclude that activation of ERK1/2 mediated by FPRL1 occurs primarily through G protein signaling. Since beta-arrestin-mediated signaling has been observed essentially for receptors coupled to G proteins other than G(i), this may be a characteristic of G(i) protein-coupled chemoattractant receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / deficiency
  • Arrestins / metabolism*
  • Cell Line
  • Endocytosis*
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • GTP-Binding Proteins / metabolism
  • Gene Expression
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Kinetics
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein Transport
  • Receptors, Formyl Peptide / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • beta-Arrestins

Substances

  • Arrestins
  • Receptors, Formyl Peptide
  • Recombinant Fusion Proteins
  • beta-Arrestins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins