Mitochondrial PKCε and MAPK Form Signaling Modules in the Murine Heart
- 8 March 2002
- journal article
- research article
- Published by Wolters Kluwer Health in Circulation Research
- Vol. 90 (4), 390-397
- https://doi.org/10.1161/01.res.0000012702.90501.8d
Abstract
Although activation of protein kinase C (PKC) ε and mitogen-activated protein kinases (MAPKs) are known to play crucial roles in the manifestation of cardioprotection, the spatial organization of PKCε signaling modules in naïve and protected myocardium remains unknown. Based on evidence that mitochondria are key mediators of the cardioprotective signal, we hypothesized that PKCε and MAPKs interact, and that they form functional signaling modules in mitochondria during cardioprotection. Both immunoblotting and immunofluorescent staining demonstrated that PKCε, ERKs, JNKs, and p38 MAPK co-localized with cardiac mitochondria. Moreover, transgenic activation of PKCε greatly increased mitochondrial PKCε expression and activity, which was concomitant with increased mitochondrial interaction of PKCε with ERKs, JNKs, and p38 as determined by co-immunoprecipitation. These complex formations appeared to be independent of PKCε activity, as the interactions were also observed in mice expressing inactive PKCε. However, although both active and inactive PKCε bound to all three MAPKs, increased phosphorylation of mitochondrial ERKs was only observed in mice expressing active PKCε but not in mice expressing inactive PKCε. Examination of potential downstream targets of mitochondrial PKCε-ERK signaling modules revealed that phosphorylation of the pro-apoptotic protein Bad was elevated in mitochondria. Together, these data show that PKCε forms subcellular-targeted signaling modules with ERKs, leading to the activation of mitochondrial ERKs. Furthermore, formation of mitochondrial PKCε-ERK modules appears to play a role in PKCε-mediated cardioprotection, in part by the phosphorylation and inactivation of Bad.Keywords
This publication has 32 references indexed in Scilit:
- Localization and Kinetics of Protein Kinase C-Epsilon Anchoring in Cardiac MyocytesBiophysical Journal, 2001
- A Single Point Mutation in the V3 Region Affects Protein Kinase Cα Targeting and Accumulation at Cell-Cell ContactsMolecular and Cellular Biology, 2001
- β-Arrestin 2: A Receptor-Regulated MAPK Scaffold for the Activation of JNK3Science, 2000
- Mitochondrial Translocation of Protein Kinase C δ in Phorbol Ester-induced Cytochrome c Release and ApoptosisJournal of Biological Chemistry, 2000
- Ischemic Preconditioning: From Adenosine Receptor to KATP ChannelAnnual Review of Physiology, 2000
- Translocation of SAPK/JNK to Mitochondria and Interaction with Bcl-xL in Response to DNA DamageJournal of Biological Chemistry, 2000
- Signaling—2000 and BeyondCell, 2000
- Organization of kinases, phosphatases, and receptor signaling complexesJCI Insight, 1999
- A Functional Role for Mitochondrial Protein Kinase Cα in Bcl2 Phosphorylation and Suppression of ApoptosisJournal of Biological Chemistry, 1998
- Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)Journal of Biological Chemistry, 1996