Circulation Research. 2002;90:390-397
Published online before print February 7, 2002, doi: 10.1161/01.RES.0000012702.90501.8D
Published online before print February 7, 2002, doi: 10.1161/01.RES.0000012702.90501.8D
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© 2002 American Heart Association, Inc.
Molecular Medicine |
Mitochondrial PKC
and MAPK Form Signaling Modules in the Murine Heart
Enhanced Mitochondrial PKC-MAPK Interactions and Differential MAPK Activation in PKC-Induced Cardioprotection
From the Department of Physiology and Biophysics and the Department of Medicine/Division of Cardiology, University of Louisville, and the Jewish Hospital Heart and Lung Institute, Louisville, Ky.
Correspondence to Peipei Ping, PhD, Department of Physiology and Biophysics and Division of Cardiology, Suite 122, Baxter Building, 570 S Preston St, Louisville, KY 40202. E-mail ping{at}ntr.net or peipeiping@hotmail.com
Although activation of protein kinase C (PKC) 
and mitogen-activated protein kinases (MAPKs) are known to play crucial roles in the manifestation of cardioprotection, the spatial organization of PKC signaling modules in naïve and protected myocardium remains unknown. Based on evidence that mitochondria are key mediators of the cardioprotective signal, we hypothesized that PKC and MAPKs interact, and that they form functional signaling modules in mitochondria during cardioprotection. Both immunoblotting and immunofluorescent staining demonstrated that PKC, ERKs, JNKs, and p38 MAPK co-localized with cardiac mitochondria. Moreover, transgenic activation of PKC greatly increased mitochondrial PKC expression and activity, which was concomitant with increased mitochondrial interaction of PKC with ERKs, JNKs, and p38 as determined by co-immunoprecipitation. These complex formations appeared to be independent of PKC activity, as the interactions were also observed in mice expressing inactive PKC. However, although both active and inactive PKC bound to all three MAPKs, increased phosphorylation of mitochondrial ERKs was only observed in mice expressing active PKC but not in mice expressing inactive PKC. Examination of potential downstream targets of mitochondrial PKC-ERK signaling modules revealed that phosphorylation of the pro-apoptotic protein Bad was elevated in mitochondria. Together, these data show that PKC forms subcellular-targeted signaling modules with ERKs, leading to the activation of mitochondrial ERKs. Furthermore, formation of mitochondrial PKC-ERK modules appears to play a role in PKC-mediated cardioprotection, in part by the phosphorylation and inactivation of Bad.
Key Words: mitochondria • protein-protein interactions • functional proteomics • signaling modules • cardioprotection
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