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J. Biol. Chem., Vol. 281, Issue 39, 28518-28528, September 29, 2006

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

Munetake Kanda¹, Yoshito Ihara¹², Hiroaki Murata, Yoshishige Urata, Takaaki Kono, Junji Yodoi^¶, Shinji Seto, Katsusuke Yano, and Takahito Kondo

From the Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute and Department of Third Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan and ^¶Department of Biological Responses, Institute for Viral Research, Kyoto University, Kyoto 606-8507, Japan

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) 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 PDGFR via a redox-dependent mechanism. We found that depletion of LMW-PTP using RNA interference enhanced the PDGF-BB-induced phosphorylation of PDGFR, indicating that LMW-PTP works for PDGFR. The enhancement of the phosphorylation of PDGFR 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 PDGFR. Thus, GRX plays an important role in PDGF-BB-dependent cell proliferation by regulating the redox state of LMW-PTP.

Received for publication, May 8, 2006 , and in revised form, June 20, 2006.

^* This work was supported in part by grants-in-aid for the 21st Century Center of Excellence (COE) program from the Ministry of Education, Science, Sports, Culture, and Technology of Japan and by grants from the Ministry of Health, Labor, and Welfare, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Tel.: 81-95-849-7099; Fax: 81-95-849-7100; E-mail: y-ihara{at}net.nagasaki-u.ac.jp.

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