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J. Biol. Chem., Vol. 280, Issue 35, 31027-31035, September 2, 2005

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The Platelet-derived Growth Factor Receptor- Phosphorylates and Activates G Protein-coupled Receptor Kinase-2

A MECHANISM FOR FEEDBACK INHIBITION^*

Jiao-Hui Wu, Robi Goswami, Luke K. Kim, William E. Miller¶, Karsten Peppel, and Neil J. Freedman||

From the Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina 27710

G protein-coupled receptor kinase-2 (GRK2) serine-phosphorylates the platelet-derived growth factor receptor- (PDGFR), and thereby diminishes signaling by the receptor. Because activation of GRK2 may involve phosphorylation of its N-terminal tyrosines by c-Src, we tested whether the PDGFR itself could tyrosine-phosphorylate and activate GRK2. To do so, we used wild type (WT) and Y857F mutant PDGFRs in HEK cells, which lack endogenous PDGFRs. The Y857F PDGFR autophosphorylates normally but does not phosphorylate exogenous substrates. Although PDGF-stimulated Y857F and WT PDGFRs activated c-Src equivalently, the WT PDGFR tyrosine-phosphorylated GKR2 60-fold more than the Y857F PDGFR in intact cells. With purified GRK2 and either WT or Y857F PDGFRs immunoprecipitated from HEK cells, GRK2 tyrosyl phosphorylation was PDGF-dependent and required the WT PDGFR, even though the WT and Y857F PDGFRs autophosphorylated equivalently. This PDGFR-mediated GRK2 tyrosyl phosphorylation enhanced GRK2 activity: GRK2-mediated seryl phosphorylation of the PDGFR was 9-fold greater for the WT than for the Y857F in response to PDGF, but equivalent when GRK2 was activated by sequential stimulation of ₂-adrenergic and PDGF- receptors. Furthermore, both PDGFR-mediated GRK2 tyrosyl phosphorylation and GRK2-mediated PDGFR seryl phosphorylation were reduced 50% in intact cells by mutation to phenylalanine of three tyrosines in the N-terminal domain of GRK2. We conclude that the activated PDGFR itself phosphorylates GRK2 tyrosyl residues and thereby activates GRK2, which then serine-phosphorylates and desensitizes the PDGFR.

Received for publication, February 8, 2005 , and in revised form, June 30, 2005.

^* This work was supported, in part, by National Institutes of Health Grants HL63288 and HL77185 (to N. J. F.) and HL64744 (to K. P.) and by an American Heart Association grant-in-aid (to N. J. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Glenn/American Federation for Aging Research Student Scholarship.

Supported by a Eugene Stead Medical Student Scholarship.

^¶ Present address: Dept. of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45267.

^|| To whom correspondence should be addressed: Duke University Medical Center, Box 3187, Durham, NC 27710. Tel.: 919-684-6873; Fax: 919-684-6870; E-mail: neil.freedman{at}duke.edu.

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