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J. Biol. Chem. 277 (17): 15021-15027

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Nitric Oxide (NO) Induces Nitration of Protein Kinase Cepsilon (PKCepsilon ), Facilitating PKCepsilon Translocation via Enhanced PKCepsilon -RACK2 Interactions
A NOVEL MECHANISM OF NO-TRIGGERED ACTIVATION OF PKCepsilon *

Zarema BalafanovaDagger §, Roberto BolliDagger §, Jun ZhangDagger §, Yuting ZhengDagger , Jason M. PassDagger §, Aruni Bhatnagar§, Xian-Liang Tang§, Ouli WangDagger , Ernest Cardwell§, and Peipei PingDagger §

From the Dagger  Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202 and the § Department of Medicine, Division of Cardiology, Louisville, Kentucky 40202

Activation of protein kinase C (PKC) epsilon  by nitric oxide (NO) has been implicated in the development of cardioprotection. However, the cellular mechanisms underlying the activation of PKCepsilon by NO remain largely unknown. Nitration of protein tyrosine residues has been shown to alter functions of a variety of proteins, and NO-derived peroxynitrite is known as a strong nitrating agent. In this investigation, we demonstrate that NO donors promote translocation and activation of PKCepsilon in an NO- and peroxynitrite-dependent fashion. NO induces peroxynitrite-mediated tyrosine nitration of PKCepsilon in rabbit cardiomyocytes in vitro, and nitrotyrosine residues were also detected on PKCepsilon in vivo in the rabbit myocardium preconditioned with NO donors. Furthermore, coimmunoprecipitation of PKCepsilon and its receptor for activated C kinase, RACK2, illustrated a peroxynitrite-dependent increase in PKCepsilon -RACK2 interactions in NO donor-treated cardiomyocytes. Moreover, using an enzyme-linked immunosorbent assay-based protein-protein interaction assay, PKCepsilon proteins treated with the peroxynitrite donor SIN-1 exhibited enhanced binding to RACK2 in an acellular environment. Our data demonstrate that post-translational modification of PKCepsilon by NO donors, namely nitration of PKCepsilon , facilitates its interaction with RACK2 and promotes translocation and activation of PKCepsilon . These findings offer a plausible novel mechanism by which NO activates the PKC signaling pathway.

* This work was supported in part by NHLBI, National Institutes of Health Grants HL-63901 and HL-65431 (to P. P.) and HL-43151, HL-55757, and HL-68088 (to R. B.), American Heart Association National Center Grant-in-aid 9750721N (to P. P.), by the Commonwealth of Kentucky Research Challenge Trust Fund, and by the Jewish Hospital Research Foundation, Louisville, Kentucky.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 570 South Preston St., Baxter Building, Suite 122, Cardiology Research, Louisville, KY 40202. Tel.: 502-852-8431; Fax: 502-852-8421; E-mail: ping@ntr.net.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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