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 1-3). 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 factor; 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 H 2O2 in PDGF signalling, and indicate a biological function of Prx II in cardiovascular disease.
| Original language | English |
|---|---|
| Pages (from-to) | 347-353 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 435 |
| Issue number | 7040 |
| DOIs | |
| State | Published - 19 May 2005 |
Bibliographical note
Funding Information: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-b 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.