Formation of protein kinase Cε-Lck signaling modules confers cardioprotection

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)499-507
Number of pages9
JournalJournal of Clinical Investigation
Volume109
Issue number4
DOIs
StatePublished - Jan 1 2002

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ping, P., Song, C., Zhang, J., Guo, Y., Cao, X., Li, R. C. X., Wu, W., Vondriska, T. M., Pass, J. M., Tang, X. L., Pierce, W. M., & Bolli, R. (2002). Formation of protein kinase Cε-Lck signaling modules confers cardioprotection. Journal of Clinical Investigation, 109(4), 499-507. https://doi.org/10.1172/JCI0213200