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Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II

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.

References

  1. Heldin, C. H. & Westermark, B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79, 1283–1316 (1999)

    CAS  Article  Google Scholar 

  2. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995)

    ADS  CAS  Article  Google Scholar 

  3. Bae, Y. S. et al. Platelet-derived growth factor-induced H2O2 production requires the activation of phosphatidylinositol 3-kinase. J. Biol. Chem. 275, 10527–10531 (2000)

    CAS  Article  Google Scholar 

  4. Kang, S. W. et al. Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-alpha. J. Biol. Chem. 273, 6297–6302 (1998)

    CAS  Article  Google Scholar 

  5. Rhee, S. G., Kang, S. W., Chang, T. S., Jeong, W. & Kim, K. Peroxiredoxin, a novel family of peroxidases. IUBMB Life 52, 35–41 (2001)

    CAS  Article  Google Scholar 

  6. Wood, Z. A., Schroder, E., Robin Harris, J. & Poole, L. B. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem. Sci. 28, 32–40 (2003)

    CAS  Article  Google Scholar 

  7. Chae, H. Z., Kim, H. J., Kang, S. W. & Rhee, S. G. Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin. Diabetes Res. Clin. Pract. 45, 101–112 (1999)

    CAS  Article  Google Scholar 

  8. Kim, H. K. et al. PDGF stimulation of inositol phospholipid hydrolysis requires PLC-γ1 phosphorylation on tyrosine residues 783 and 1254. Cell 65, 435–441 (1991)

    CAS  Article  Google Scholar 

  9. Baxter, R. M., Secrist, J. P., Vaillancourt, R. R. & Kazlauskas, A. Full activation of the platelet-derived growth factor β-receptor kinase involves multiple events. J. Biol. Chem. 273, 17050–17055 (1998)

    CAS  Article  Google Scholar 

  10. Rhee, S. G. & Bae, Y. S. Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem. 272, 15045–15048 (1997)

    CAS  Article  Google Scholar 

  11. Sekiya, F., Poulin, B., Kim, Y. J. & Rhee, S. G. Mechanism of tyrosine phosphorylation and activation of phospholipase C-γ1. Tyrosine 783 phosphorylation is not sufficient for lipase activation. J. Biol. Chem. 279, 32181–32190 (2004)

    CAS  Article  Google Scholar 

  12. Saito, S. et al. Ligand-independent trans-activation of the platelet-derived growth factor receptor by reactive oxygen species requires protein kinase C-δ and c-Src. J. Biol. Chem. 277, 44695–44700 (2002)

    CAS  Article  Google Scholar 

  13. Rosado, J. A. et al. Hydrogen peroxide generation induces pp60src activation in human platelets: evidence for the involvement of this pathway in store-mediated calcium entry. J. Biol. Chem. 279, 1665–1675 (2004)

    CAS  Article  Google Scholar 

  14. Yang, K. S. et al. Inactivation of human peroxiredoxin I during catalysis as the result of the oxidation of the catalytic site cysteine to cysteine-sulfinic acid. J. Biol. Chem. 277, 38029–38036 (2002)

    CAS  Article  Google Scholar 

  15. Rhee, S. G., Bae, Y. S., Lee, S. R. & Kwon, J. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci STKE 2000, PE1 (2000).

  16. Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993)

    ADS  CAS  Article  Google Scholar 

  17. Ferns, G. A. et al. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 253, 1129–1132 (1991)

    ADS  CAS  Article  Google Scholar 

  18. Persson, C. et al. Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase. Mol. Cell. Biol. 24, 2190–2201 (2004)

    CAS  Article  Google Scholar 

  19. Lee, T. H. et al. Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice. Blood 101, 5033–5038 (2003)

    CAS  Article  Google Scholar 

  20. Kang, S. W. et al. Cytosolic peroxiredoxin attenuates the activation of Jnk and p38 but potentiates that of Erk in Hela cells stimulated with tumor necrosis factor-α. J. Biol. Chem. 279, 2535–2543 (2004)

    CAS  Article  Google Scholar 

  21. Ohmi, K. et al. A novel aortic smooth muscle cell line obtained from p53 knock out mice expresses several differentiation characteristics. Biochem. Biophys. Res. Commun. 238, 154–158 (1997)

    CAS  Article  Google Scholar 

  22. Schober, A. et al. Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice. Circulation 109, 380–385 (2004)

    CAS  Article  Google Scholar 

  23. Woo, H. A. et al. Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteine-containing sequence. J. Biol. Chem. 278, 47361–47364 (2003)

    CAS  Article  Google Scholar 

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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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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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