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Molecular Pharmacology

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Research ArticleArticle

Reciprocal Regulation of the Platelet-Derived Growth Factor Receptor-β and G Protein-Coupled Receptor Kinase 5 by Cross-Phosphorylation: Effects on Catalysis

Xinjiang Cai, Jiao-Hui Wu, Sabrina T. Exum, Martin Oppermann, Richard T. Premont, Sudha K. Shenoy and Neil J. Freedman
Molecular Pharmacology March 2009, 75 (3) 626-636; DOI: https://doi.org/10.1124/mol.108.050278
Xinjiang Cai
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Jiao-Hui Wu
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Sabrina T. Exum
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Martin Oppermann
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Richard T. Premont
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Sudha K. Shenoy
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Neil J. Freedman
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Abstract

Signaling by the platelet-derived growth factor receptor-β (PDGFRβ) is diminished when the PDGFRβ is phosphorylated on seryl residues by G protein-coupled receptor kinase-5 (GRK5), but mechanisms for GRK5 activation by the PDGFRβ remain obscure. We therefore tested whether the PDGFRβ is able to tyrosine-phosphorylate and thereby activate GRK5. Purified GRK5 was tyrosine-phosphorylated by the wild-type PDGFRβ to a stoichiometry of 0.8 mol phosphate/mol GRK5, an extent ∼5 times greater than observed with a Y857F PDGFRβ mutant that fails to phosphorylate exogenous substrates but autophosphorylates and activates Src normally. The degree of PDGFRβ-mediated phosphorylation of GRK5 correlated with GRK5 activity, as assessed by seryl phosphorylation of the PDGFRβ in purified protein preparations, in intact cells expressing a tyrosine-to-phenylalanine GRK5 mutant, and in GRK5 peptide phosphorylation assays. However, tyrosyl phosphorylation of GRK5 was not necessary for GRK5-mediated phosphorylation of the β2-adrenergic receptor, even though β2-adrenergic receptor activation promoted tyrosyl phosphorylation of GRK5 in smooth muscle cells. Phosphorylation of the PDGFRβ by GRK5 in smooth muscle cells or in purified protein preparations reduced PDGFRβ-mediated peptide phosphorylation. In contrast, phosphorylation of GRK5 by the PDGFRβ enhanced the Vmax of GRK5-mediated peptide phosphorylation, by 3.4-fold, without altering the GRK5 KM for peptide. We conclude that GRK5 tyrosyl phosphorylation is required for the activation of GRK5 by the PDGFRβ, but not by the β2-adrenergic receptor, and that by activating GRK5, the PDGFRβ triggers its own desensitization.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL77185, HL73005, HL80525]; the National Institutes of Health National Institute on Drug Abuse [Grant DA016347]; and the American Heart Association, Mid-Atlantic Affiliate [Grant-in-Aid 0655464U and Postdoctoral Fellowship 0625403U].

  • ABBREVIATIONS: PDGFRβ, platelet-derived growth factor receptor-β; β2AR, β2-adrenergic receptor; ChiR, chimeric colony stimulating factor-1/platelet-derived growth factor-β receptor; CSF-1, colony stimulating factor-1; EGFR, epidermal growth factor receptor; GRK, (heterotrimeric) G protein-coupled receptor kinase; IB, immunoblot; IP, immunoprecipitation; ISO, (-)isoproterenol; PDGF, platelet-derived growth factor; SMC, smooth muscle cell; WT, wild-type; Y4F, G protein-coupled receptor kinase-5 mutant with four tyrosine-to-phenylalanine point mutations; PCR, polymerase chain reaction; HEK, human embryonic kidney; PAGE, polyacrylamide gel electrophoresis; AG1295, 6,7-dimethyl-2-phenylquinoxaline.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.

    • Received July 4, 2008.
    • Accepted December 17, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (3)
Molecular Pharmacology
Vol. 75, Issue 3
1 Mar 2009
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Research ArticleArticle

Reciprocal Regulation of the Platelet-Derived Growth Factor Receptor-β and G Protein-Coupled Receptor Kinase 5 by Cross-Phosphorylation: Effects on Catalysis

Xinjiang Cai, Jiao-Hui Wu, Sabrina T. Exum, Martin Oppermann, Richard T. Premont, Sudha K. Shenoy and Neil J. Freedman
Molecular Pharmacology March 1, 2009, 75 (3) 626-636; DOI: https://doi.org/10.1124/mol.108.050278

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Research ArticleArticle

Reciprocal Regulation of the Platelet-Derived Growth Factor Receptor-β and G Protein-Coupled Receptor Kinase 5 by Cross-Phosphorylation: Effects on Catalysis

Xinjiang Cai, Jiao-Hui Wu, Sabrina T. Exum, Martin Oppermann, Richard T. Premont, Sudha K. Shenoy and Neil J. Freedman
Molecular Pharmacology March 1, 2009, 75 (3) 626-636; DOI: https://doi.org/10.1124/mol.108.050278
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