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Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2.

Publication ,  Journal Article
Wu, J-H; Goswami, R; Cai, X; Exum, ST; Huang, X; Zhang, L; Brian, L; Premont, RT; Peppel, K; Freedman, NJ
Published in: J Biol Chem
December 8, 2006

Smooth muscle cell (SMC) proliferation and migration are substantially controlled by the platelet-derived growth factor receptor-beta (PDGFRbeta), 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 PDGFRbeta activation engendered down-regulation of GRK5, but not GRK2; moreover, GRK5 and PDGFRbeta 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 PDGFRbeta seryl phosphorylation by 3-fold and reduced PDGFRbeta-promoted phosphoinositide hydrolysis, thymidine incorporation, and overall PDGFRbeta tyrosyl phosphorylation by approximately 35%. Physiologic SMC GRK5 activity also increased PDGFRbeta association with the phosphatase Shp2 (8-fold), enhanced phosphorylation of PDGFRbeta Tyr(1009) (the docking site for Shp2), and reduced phosphorylation of PDGFRbeta Tyr(1021). Consistent with having increased PDGFRbeta-associated Shp2 activity, GRK5-expressing SMCs demonstrated greater PDGF-induced Src activation than GRK5-null cells. GRK5-mediated desensitization of PDGFRbeta inositol phosphate signaling was diminished by Shp2 knock-down or impairment of PDGFRbeta/Shp2 association. In contrast to GRK5, physiologic GRK2 activity did not alter PDGFRbeta/Shp2 association. Finally, purified GRK5 effected agonist-dependent seryl phosphorylation of partially purified PDGFRbetas. We conclude that GRK5 mediates the preponderance of PDGF-promoted seryl phosphorylation of the PDGFRbeta in SMCs, and, through mechanisms involving Shp2, desensitizes PDGFRbeta inositol phosphate signaling and enhances PDGFRbeta-triggered Src activation.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 8, 2006

Volume

281

Issue

49

Start / End Page

37758 / 37772

Location

United States

Related Subject Headings

  • Transfection
  • Recombinant Proteins
  • Receptor, Platelet-Derived Growth Factor beta
  • Rabbits
  • RNA Interference
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Muscle, Smooth, Vascular
 

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Wu, J.-H., Goswami, R., Cai, X., Exum, S. T., Huang, X., Zhang, L., … Freedman, N. J. (2006). Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2. J Biol Chem, 281(49), 37758–37772. https://doi.org/10.1074/jbc.M605756200
Wu, Jiao-Hui, Robi Goswami, Xinjiang Cai, Sabrina T. Exum, Xuewei Huang, Lisheng Zhang, Leigh Brian, Richard T. Premont, Karsten Peppel, and Neil J. Freedman. “Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2.J Biol Chem 281, no. 49 (December 8, 2006): 37758–72. https://doi.org/10.1074/jbc.M605756200.
Wu, Jiao-Hui, et al. “Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2.J Biol Chem, vol. 281, no. 49, Dec. 2006, pp. 37758–72. Pubmed, doi:10.1074/jbc.M605756200.
Wu J-H, Goswami R, Cai X, Exum ST, Huang X, Zhang L, Brian L, Premont RT, Peppel K, Freedman NJ. Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2. J Biol Chem. 2006 Dec 8;281(49):37758–37772.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 8, 2006

Volume

281

Issue

49

Start / End Page

37758 / 37772

Location

United States

Related Subject Headings

  • Transfection
  • Recombinant Proteins
  • Receptor, Platelet-Derived Growth Factor beta
  • Rabbits
  • RNA Interference
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Muscle, Smooth, Vascular