Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor. Academic Article uri icon

Overview

abstract

  • G protein-coupled receptor kinase-2 (GRK2) can phosphorylate and desensitize the platelet-derived growth factor receptor-beta (PDGFRbeta) in heterologous cellular systems. To determine whether GRK2 regulates the PDGFRbeta in physiologic systems, we examined PDGFRbeta signaling in mouse embryonic fibroblasts from GRK2-null and cognate wild type mice. To discern a mechanism by which GRK2-mediated phosphorylation can desensitize the PDGFRbeta, but not the epidermal growth factor receptor (EGFR), we investigated effects of GRK2-mediated phosphorylation on the association of the PDGFRbeta with the Na(+)/H(+) exchanger regulatory factor (NHERF), a protein shown to potentiate dimerization of the PDGFRbeta, but not the EGFR. Physiologic expression of GRK2 diminished (a) phosphoinositide hydrolysis elicited through the PDGFRbeta but not heterotrimeric G proteins; (b) Akt activation evoked by the PDGFRbeta but not the EGFR; and (c) PDGF-induced tyrosyl phosphorylation of the PDGFRbeta itself. PDGFRbeta desensitization by physiologically expressed GRK2 correlated with a 2.5-fold increase in PDGF-promoted PDGFRbeta seryl phosphorylation. In 293 cells, GRK2 overexpression reduced PDGFRbeta/NHERF association by 60%. This effect was reproduced by S1104D mutation of the PDGFRbeta, which also diminished PDGFRbeta activation and signaling (like the S1104A mutation) to an extent equivalent to that achieved by GRK2-mediated PDGFRbeta phosphorylation. GRK2 overexpression desensitized only the wild type but not the S1104A PDGFRbeta. We conclude that GRK2-mediated PDGFRbeta seryl phosphorylation plays an important role in desensitizing the PDGFRbeta in physiologic systems. Furthermore, this desensitization appears to involve GRK2-mediated phosphorylation of PDGFRbeta Ser(1104), with consequent dissociation of the PDGFRbeta from NHERF.

publication date

  • July 22, 2004

Research

keywords

  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoproteins
  • Receptor, Platelet-Derived Growth Factor beta
  • Signal Transduction

Identity

Scopus Document Identifier

  • 4744349417

Digital Object Identifier (DOI)

  • 10.1074/jbc.M403274200

PubMed ID

  • 15271984

Additional Document Info

volume

  • 279

issue

  • 40