Glutaredoxin Modulates Platelet-derived Growth Factor-dependent Cell Signaling by Regulating the Redox Status of Low Molecular Weight Protein-tyrosine Phosphatase

Glutaredoxin (GRX) is a glutathione-disulfide oxidoreductase involved in various cellular functions, including the redox-dependent regulation of certain integral proteins. Here we demonstrated that overexpression of GRX suppressed the proliferation of myocardiac H9c2 cells treated with platelet-deri...

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Veröffentlicht in:The Journal of biological chemistry 2006-09, Vol.281 (39), p.28518-28528
Hauptverfasser: Kanda, Munetake, Ihara, Yoshito, Murata, Hiroaki, Urata, Yoshishige, Kono, Takaaki, Yodoi, Junji, Seto, Shinji, Yano, Katsusuke, Kondo, Takahito
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Sprache:eng
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Zusammenfassung:Glutaredoxin (GRX) is a glutathione-disulfide oxidoreductase involved in various cellular functions, including the redox-dependent regulation of certain integral proteins. Here we demonstrated that overexpression of GRX suppressed the proliferation of myocardiac H9c2 cells treated with platelet-derived growth factor (PDGF)-BB. After stimulation with PDGF-BB, the phosphorylation of PDGF receptor (PDGFR) β was suppressed in GRX gene-transfected cells, compared with controls. Conversely, the phosphorylation was enhanced by depletion of GRX by RNA interference. In this study we focused on the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in the dephosphorylation of PDGFRβ via a redox-dependent mechanism. We found that depletion of LMW-PTP using RNA interference enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, indicating that LMW-PTP works for PDGFRβ. The enhancement of the phosphorylation of PDGFRβ was well correlated with inactivation of LMW-PTP by cellular peroxide generated in the cells stimulated with PDGF-BB. In vitro, with hydrogen peroxide treatment, LMW-PTP showed decreased activity with the concomitant formation of dithiothreitol-reducible oligomers. GRX protected LMW-PTP from hydrogen peroxide-induced oxidation and inactivation in concert with glutathione, NADPH, and glutathione disulfide reductase. This strongly suggests that retention of activity of LMW-PTP by enhanced GRX expression suppresses the proliferation of cells treated with PDGF-BB via enhanced dephosphorylation of PDGFRβ. Thus, GRX plays an important role in PDGF-BB-dependent cell proliferation by regulating the redox state of LMW-PTP.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M604359200