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Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.

Publication ,  Journal Article
Freeman, JL; De La Cruz, EM; Pollard, TD; Lefkowitz, RJ; Pitcher, JA
Published in: J Biol Chem
August 7, 1998

G protein-coupled receptor kinases (GRKs) initiate pathways leading to the desensitization of agonist-occupied G-protein-coupled receptors (GPCRs). Here we report that the cytoskeletal protein actin binds and inhibits GRK5. Actin inhibits the kinase activity directly, reducing GRK5-mediated phosphorylation of both membrane-bound GPCRs and soluble substrates. GRK5 binds actin monomers with a Kd of 0.6 microM and actin filaments with a Kd of 0. 2 microM. Mutation of 6 amino acids near the amino terminus of GRK5 eliminates actin-mediated inhibition of GRK5. Calmodulin has previously been shown to bind to the amino terminus of GRK5 (Pronin, A. N., and Benovic, J. L. (1997) J. Biol. Chem. 272, 3806-3812) and here we show calmodulin displaces GRK5 from actin. Calmodulin inhibits GRK5-mediated phosphorylation of GPCRs, but not soluble substrates such as casein. Thus in the presence of actin, calmodulin determines the substrate specificity of GRK5 by preferentially allowing phosphorylation of soluble substrates over membrane-bound substrates.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 7, 1998

Volume

273

Issue

32

Start / End Page

20653 / 20657

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Rhodopsin
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphorylation
  • Mutation
  • Molecular Sequence Data
  • GTP-Binding Proteins
  • G-Protein-Coupled Receptor Kinase 5
 

Citation

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Freeman, J. L., De La Cruz, E. M., Pollard, T. D., Lefkowitz, R. J., & Pitcher, J. A. (1998). Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin. J Biol Chem, 273(32), 20653–20657. https://doi.org/10.1074/jbc.273.32.20653
Freeman, J. L., E. M. De La Cruz, T. D. Pollard, R. J. Lefkowitz, and J. A. Pitcher. “Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.J Biol Chem 273, no. 32 (August 7, 1998): 20653–57. https://doi.org/10.1074/jbc.273.32.20653.
Freeman JL, De La Cruz EM, Pollard TD, Lefkowitz RJ, Pitcher JA. Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin. J Biol Chem. 1998 Aug 7;273(32):20653–7.
Freeman, J. L., et al. “Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.J Biol Chem, vol. 273, no. 32, Aug. 1998, pp. 20653–57. Pubmed, doi:10.1074/jbc.273.32.20653.
Freeman JL, De La Cruz EM, Pollard TD, Lefkowitz RJ, Pitcher JA. Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin. J Biol Chem. 1998 Aug 7;273(32):20653–20657.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 7, 1998

Volume

273

Issue

32

Start / End Page

20653 / 20657

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Rhodopsin
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphorylation
  • Mutation
  • Molecular Sequence Data
  • GTP-Binding Proteins
  • G-Protein-Coupled Receptor Kinase 5