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 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.

Phosphoproteins regulated by heat stress in rice leaves

“…Peroxiredoxins have diverse functions in cellular defense-signaling pathways [25], and 2-Cys peroxiredoxin plays direct roles in cellular-signaling events [25-27]. Although its functional significance is unclear, heat-induced dephosphorylation of 2-Cys peroxiredoxin may be involved in the transduction of cellular-signaling.…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Over-oxidation of Prx is believed to occur when H 2 O 2 concentrations exceed the capacity of Prx regeneration by the Trx system, and originally was proposed to act as a "floodgate" to promote H 2 O 2 signaling [61]. While a small portion of PrxI and II have been reported to be hyper-oxidized in response to physiological stimuli, PrxII dampens signaling through interactions with the PDGF receptor in the absence of hyper-oxidation [62].…”

“…Originally these enzymes were thought to be relatively weak scavengers of H 2 O 2 , but recent work shows that are as active as peroxidases as either catalase or glutathione peroxidase. What distinguishes peroxiredoxins from other peroxidases is their interaction with numerous regulatory proteins, including c-Abl, c-Myc, JNK, and the PDGF receptor [62,[68][69][70][71]. Little is known about how the oxidation state of Prxs influences protein-protein interactions, but one intriguing possibility is that oxidation state of peroxiredoxins may influence the subcellular location or activity of interacting factors.…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Based on observations that NOX-dependent signaling is in many cases mitigated by H 2 O 2 -degrading enzymes such as catalase or peroxiredoxins (39,55,56), it is commonly assumed that H 2 O 2 is the active signaling molecule in these signaling pathways. Indeed, H 2 O 2 readily oxidizes cysteine thiolate moieties, e.g.…”

“…Additionally, NOX-mediated effects on e.g. cell proliferation or migration also depend on strict spatial localization of NOX activation in association with the cytoskeleton (70,71) or in membrane rafts (43,72,73), and on direct interactions with target proteins (3,43,55). This allows for effective oxidative signaling in the presence of abundant cytosolic antioxidant mechanisms (Cu/Zn SOD, GSH peroxidase), and assures confined oxidant production and target specificity.…”