Formation of protein kinase Cε-Lck signaling modules confers cardioprotection
Peipei Ping, … , William M. Pierce, Roberto Bolli
Peipei Ping, … , William M. Pierce, Roberto Bolli
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):499-507. https://doi.org/10.1172/JCI13200.
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Article

Formation of protein kinase Cε-Lck signaling modules confers cardioprotection

Abstract

The ε isoform of protein kinase C (PKCε) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCε signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCε orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCε. In cardiac cells, PKCε interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCε or by ischemic preconditioning enhances the formation of PKCε-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCε-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCε-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCε-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.

Authors

Peipei Ping, Changxu Song, Jun Zhang, Yiru Guo, Xinan Cao, Richard C.X. Li, Wenjian Wu, Thomas M. Vondriska, Jason M. Pass, Xian-Liang Tang, William M. Pierce, Roberto Bolli

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Figure 5

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Ischemic preconditioning (PC) and PKCε-induced cardioprotection are asso...
Ischemic preconditioning (PC) and PKCε-induced cardioprotection are associated with increased formation of PKCε-Lck signaling modules. (a) Cardiac samples obtained from wild-type mice that underwent an ischemic PC protocol (six cycles of 4-minute coronary occlusion/ reperfusion) exhibited increased colocalization of Lck with PKCε (upper panel) and enhanced Lck phosphorylation activity (lower panel), indicating that ischemic PC was associated with increased formation of PKCε-Lck signaling modules. *P < 0.05 vs. control. (b) Myocardial tissue samples obtained from PKCε transgenic mice displayed increased colocalization of Lck with PKCε (upper panel) and enhanced Lck phosphorylation activity (lower panel), indicating that PKCε-induced cardioprotection was concomitant with increased formation of PKCε-Lck signaling modules. *P < 0.05 vs. wild-type. (c) Characterization of Lck–/– mice and PKCε-Lck–/– mice. The PKCε expression in Lck–/– mice was similar to that in wild-type mice, indicating that ablation of the Lck gene did not affect PKCε expression (upper panels). In PKCε-Lck–/– mice, increased expression of PKCε was preserved whereas Lck expression was absent (lower panels). (d) Preserved PKCε activation by ischemic PC in Lck–/– mice. Ischemic PC induced significant activation of PKCε in Lck mice, indicating that ablation of the Lck–/– gene did not affect activation of PKCε. All tissue samples were harvested 30 minutes after ischemic PC. *P < 0.05 vs. Lck–/– control. Data are mean ± SEM.