Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II.
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 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 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.
Choi
Min Hee
MH
Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea.
Lee
In Kyung
IK
Kim
Gyung Whan
GW
Kim
Bang Ul
BU
Han
Ying-Hao
YH
Yu
Dae-Yeul
DY
Park
Hye Sun
HS
Kim
Kyung Yong
KY
Lee
Jong Seo
JS
Choi
Chulhee
C
Bae
Yun Soo
YS
Lee
Byung In
BI
Rhee
Sue Goo
SG
Kang
Sang Won
SW
D000818:Animals; D001011:Aorta / Q000166:cytology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010544:Peroxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011485:Protein Binding; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D010982:Platelet-Derived Growth Factor; D019000:Phosphotyrosine; D010544:Peroxidases; D054464:Peroxiredoxins; D017479:Receptors, Platelet-Derived Growth Factor