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Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II

Nature volume 435, pages 347–353 (2005)Cite this article

Abstract

Platelet-derived growth factor (PDGF) is a potent mitogenic and migratory factor that regulates the tyrosine phosphorylation of a variety of signalling proteins via intracellular production of H2O2 (refs 1, 2–3). Mammalian 2-Cys peroxiredoxin type II (Prx II; gene symbol Prdx2) is a cellular peroxidase that eliminates endogenous H2O2 produced in response to growth factors such as PDGF and epidermal growth factor4; however, its involvement in growth factor signalling is largely unknown. Here we show that Prx II is a negative regulator of PDGF signalling. Prx II deficiency results in increased production of H2O2, enhanced activation of PDGF receptor (PDGFR) and phospholipase Cγ1, and subsequently increased cell proliferation and migration in response to PDGF. These responses are suppressed by expression of wild-type Prx II, but not an inactive mutant. Notably, Prx II is recruited to PDGFR upon PDGF stimulation, and suppresses protein tyrosine phosphatase inactivation. Prx II also leads to the suppression of PDGFR activation in primary culture and a murine restenosis model, including PDGF-dependent neointimal thickening of vascular smooth muscle cells. These results demonstrate a localized role for endogenous H2O2 in PDGF signalling, and indicate a biological function of Prx II in cardiovascular disease.

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Figure 1: Prx II is a physiological negative regulator of PDGF signalling.
Figure 2: Phosphorylation-site-selective regulation of PDGFR activation by Prx II.
Figure 3: Interaction of Prx II with activated PDGFR-β.
Figure 4: In vivo function of Prx II during restenosis in injured carotid artery.

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Acknowledgements

We thank J. B. Kwon, E. S. Oh and T. H. Lee for reagents and discussions; J. Kim and I. C. Baines for critically reading the manuscript; G. P. Nolan for pBMN retroviral plasmids; A. Kazlauskas for providing HepG2 cells overexpressing PDGFR-β wild type; and D. J. Lee for immunofluorescence staining. We also thank I. H. Lee, H. I. Park and researchers in Labfrontier Life Science Institute for technical assistance. This work was supported by Korea Science and Engineering Foundation through the Center for Cell Signalling Research in Ewha Womans University and by a grant from the Functional Proteomics Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of the Korean government. M.H.C. is supported by a Brain Korea 21 grant from the Ministry of Education and Human Resources Development.

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Author notes

  1. Min Hee Choi and In Kyung Lee: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Womans University, Seoul, 120-750, Korea

    Min Hee Choi, In Kyung Lee, Bang Ul Kim, Hye Sun Park, Chulhee Choi, Yun Soo Bae & Sang Won Kang

  2. Department of Neurology, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Gyung Whan Kim & Byung In Lee

  3. Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Korea

    Ying-Hao Han & Dae-Yeul Yu

  4. Life Science Institute, Labfrontier Co. Ltd., KSBC building, san 111-8, Iui-dong, Paldal-gu, Suwon, Kyunggi-do, 442-766, Korea

    Kyung Yong Kim & Jong Seo Lee

  5. Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Sue Goo Rhee

  6. Department of Biosystems, KAIST, Daejeon, 305-701, Korea

    Chulhee Choi

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Correspondence to Sue Goo Rhee or Sang Won Kang.

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Supplementary information

Supplementary Methods

This document contains methods sections: (1) cell proliferation, migration and measurement of inositol phosphates; (2) immunoprecipitation and in vitro receptor tyrosine kinase assay; (3) relevant references. (PDF 23 kb)

Supplementary Figure Legends

This document contains the legends for Supplementary Figs 1-7. (PDF 23 kb)

Supplementary Figure 1

Analysis of epidermal growth factor (EGF) signalling in wt and Prx II(-/-) MEFs (a); suppression by Prx II of MEF migration (b). (PDF 221 kb)

Supplementary Figure 2

Catalase inhibition and glutathione depletion result in the elevation of PDGF-induced H2O2 production. (PDF 19 kb)

Supplementary Figure 3

Specificity of the phospho-specific antibodies against tyrosine residues of PDGFRβ. (PDF 161 kb)

Supplementary Figure 4

Characterization of the commercial anti-phospho-PDGFRβ antibodies. (PDF 224 kb)

Supplementary Figure 5

Immunoblot analysis of PDGFR phosphorylation in H2O2-treated MEFs overexpressing Prx II-wt. (PDF 102 kb)

Supplementary Figure 6

Tyrosine phosphorylation of PDGFR in NIH3T3 cells overexpressing Prx II-wt. (PDF 168 kb)

Supplementary Figure 7

Characterization for mouse PDGF-neutralizing activity of anti-PDGF antibody. (PDF 87 kb)

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Choi, M., Lee, I., Kim, G. et al. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435, 347–353 (2005). https://doi.org/10.1038/nature03587

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