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Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus.

Abstract
The binding of CC chemokines to CC chemokine receptor 5 (CCR5) triggers cellular responses that, generally, are only transient in nature. To explore the potential role of G protein-coupled receptor kinases (GRKs) in the regulation of CCR5, we performed phosphorylation experiments in a rat basophilic leukemia cell line stably expressing CCR5. The ability of various CCR5 ligands to stimulate calcium mobilization in these cells correlated with their ability to induce receptor phosphorylation, desensitization, internalization, and GRK association with the receptor. Aminooxypentane-RANTES, a potent inhibitor of human immunodeficiency virus infection, has been proposed to act through enhanced CCR5 internalization and inhibition of receptor recycling. Aminooxypentane-RANTES profoundly induced CCR5 phosphorylation, but had no effect on CCR1. In permeabilized rat basophilic leukemia CCR5 cells, monoclonal antibodies with specificity for GRK2/3 inhibited RANTES-induced receptor phosphorylation. Consistent with a role for these kinases in CCR5 regulation, 1-2 x 10(5) copies of GRK2 or GRK3 were found to be expressed in peripheral blood leukocytes. Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. This study demonstrates that chemokines differ in their ability to induce CCR5 phosphorylation and desensitization and provides a molecular mechanism for the agonist-induced attenuation of CCR5 signaling.
AuthorsM Oppermann, M Mack, A E Proudfoot, H Olbrich
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 13 Pg. 8875-85 (Mar 26 1999) ISSN: 0021-9258 [Print] United States
PMID10085131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CCR1 protein, human
  • Ccr1 protein, rat
  • Chemokine CCL5
  • Chemokines, CC
  • Enzyme Inhibitors
  • Ligands
  • Phosphoamino Acids
  • Receptors, CCR1
  • Receptors, CCR5
  • Receptors, Chemokine
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • G-Protein-Coupled Receptor Kinase 3
  • GRK3 protein, human
  • Grk3 protein, rat
  • beta-Adrenergic Receptor Kinases
  • Calcium
Topics
  • Animals
  • Calcium (metabolism)
  • Cell Line
  • Chemokine CCL5 (analogs & derivatives, pharmacology)
  • Chemokines, CC (metabolism)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Enzyme Inhibitors (pharmacology)
  • G-Protein-Coupled Receptor Kinase 3
  • Ligands
  • Mutation (genetics)
  • Phosphoamino Acids (analysis)
  • Phosphorylation
  • Protein Kinase C (antagonists & inhibitors)
  • Protein Serine-Threonine Kinases
  • Rats
  • Receptor Protein-Tyrosine Kinases (metabolism)
  • Receptors, CCR1
  • Receptors, CCR5 (genetics, metabolism)
  • Receptors, Chemokine (metabolism)
  • Signal Transduction
  • beta-Adrenergic Receptor Kinases

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