Regulating Peroxide Signaling

Abstract

Platelet-derived growth factor (PDGF) stimulates the production of H 2 O 2 , which acts as a second messenger to regulate the tyrosine phosphorylation of various proteins. Choi et al . found that, in mouse embryonic fibroblasts (MEFs) lacking the cellular peroxidase 2-Cys peroxiredoxin type II (Prx II -/- MEFs), PDGF elicited twice the peak H 2 O 2 production that it elicited from wild-type MEFs. PDGF-induced total tyrosine phosphorylation and phosphorylation of tyrosine residues of phospholipase Cγ1 (PLC-γ1) that are required for its activation were also enhanced in Prx II -/- MEFs. Retroviral expression of human Prx II in Prx II -/- MEFs inhibited PDGF-induced tyrosine phosphorylation and inositol-1,4,5-trisphosphate production, as well as attenuating PDGF-stimulated cell proliferation, migration, and adhesion. The PDGF receptor (PDGFR) in Prx II -/- MEFs was hyperphosphorylated on residues involved in the activation of PDGFR kinase activity (an effect that was inhibited by expression of Prx II) and showed an increased in vitro phosphorylation of PLC-γ1. PDGF promoted the association of Prx II with PDGFR-β, where it appeared to attenuate the oxidative inactivation of protein tyrosine phosphatases. In a mouse model of restenosis (in which vascular smooth muscle cells undergo PDGF-dependent proliferation and migration), Prx II -/- mice showed increased thickening of the innermost layer of injured carotid arteries compared with wild-type mice. Thus, Prx II appears to regulate PDGF signaling and to play a role in cardiovascular lesions that occur in atherosclerosis or following injury. M. H. Choi, I. K. Lee, G. W. Kim, B. U. Kim, Y.-H. Han, D.-Y. Yu, H. S. Park, K. Y. Kim, J. S. Lee, C. Choi, Y. S. Bae, B. I. Lee, S. G. Rhee, S. W. Kang, Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435 , 347-353 (2005). [PubMed]