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Nature 435, 347-353 (19 May 2005) | doi:10.1038/nature03587; Received 18 January 2005; Accepted 29 March 2005

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Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II

Min Hee Choi1,7, In Kyung Lee1,7, Gyung Whan Kim2, Bang Ul Kim1, Ying-Hao Han3, Dae-Yeul Yu3, Hye Sun Park1, Kyung Yong Kim4, Jong Seo Lee4, Chulhee Choi1,6, Yun Soo Bae1, Byung In Lee2, Sue Goo Rhee5 & Sang Won Kang1

  1. Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea
  2. Department of Neurology, Yonsei University College of Medicine, Seoul 120-752, Korea
  3. Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Korea
  4. Life Science Institute, Labfrontier Co. Ltd., KSBC building, san 111-8, Iui-dong, Paldal-gu, Suwon, Kyunggi-do 442-766, Korea
  5. Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  6. Department of Biosystems, KAIST, Daejeon 305-701, Korea
  7. These authors contributed equally to this work

Correspondence to: Sue Goo Rhee5Sang Won Kang1 Correspondence and requests for materials should be addressed to S.W.K. (Email: kangsw@ewha.ac.kr) or S.G.R. (Email: sgrhee@nih.gov).

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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 Cgamma1, 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.