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J. Biol. Chem., Vol. 281, Issue 49, 37758-37772, December 8, 2006

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Regulation of the Platelet-derived Growth Factor Receptor- by G Protein-coupled Receptor Kinase-5 in Vascular Smooth Muscle Cells Involves the Phosphatase Shp2^*

From the Departments of Medicine (Cardiology) and Cell Biology, Duke University, Medical Center, Durham, North Carolina 27710

Smooth muscle cell (SMC) proliferation and migration are substantially controlled by the platelet-derived growth factor receptor- (PDGFR), which can be regulated by the Ser/Thr kinase G protein-coupled receptor kinase-2 (GRK2). In mouse aortic SMCs, however, we found that prolonged PDGFR activation engendered down-regulation of GRK5, but not GRK2; moreover, GRK5 and PDGFR were coordinately up-regulated in SMCs from atherosclerotic arteries. With SMCs from GRK5 knock-out and cognate wild type mice (five of each), we found that physiologic expression of GRK5 increased PDGF-promoted PDGFR seryl phosphorylation by 3-fold and reduced PDGFR-promoted phosphoinositide hydrolysis, thymidine incorporation, and overall PDGFR tyrosyl phosphorylation by 35%. Physiologic SMC GRK5 activity also increased PDGFR association with the phosphatase Shp2 (8-fold), enhanced phosphorylation of PDGFR Tyr¹⁰⁰⁹ (the docking site for Shp2), and reduced phosphorylation of PDGFR Tyr¹⁰²¹. Consistent with having increased PDGFR-associated Shp2 activity, GRK5-expressing SMCs demonstrated greater PDGF-induced Src activation than GRK5-null cells. GRK5-mediated desensitization of PDGFR inositol phosphate signaling was diminished by Shp2 knock-down or impairment of PDGFR/Shp2 association. In contrast to GRK5, physiologic GRK2 activity did not alter PDGFR/Shp2 association. Finally, purified GRK5 effected agonist-dependent seryl phosphorylation of partially purified PDGFRs. We conclude that GRK5 mediates the preponderance of PDGF-promoted seryl phosphorylation of the PDGFR in SMCs, and, through mechanisms involving Shp2, desensitizes PDGFR inositol phosphate signaling and enhances PDGFR-triggered Src activation.

Received for publication, June 15, 2006 , and in revised form, September 18, 2006.

^* This work was supported in part by National Institutes of Health Grants HL77185, HL63288, and HL73005 (to N. J. F.), HL64744 (to K. P.), and GM59989 and DA16347 (to R. T. P.) as well as 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.

¹ Supported by a Glenn/AFAR medical student scholarship.

² Supported by a Eugene Stead medical student scholarship.

³ To whom correspondence may be addressed: Jefferson Medical College 1025 Walnut St., Rm. 311 Philadelphia, PA 19107. E-mail: karsten.peppel{at}jefferson.edu. ⁴ To whom correspondence may be addressed: Box 3187 Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-6873; Fax: 919-684-6870. E-mail: neil.freedman{at}duke.edu.

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