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Functional proteomic analysis of a three-tier PKC-Akt-eNOS signaling module in cardiac protection

¹Division of Cardiology, Departments of Physiology and Medicine, University of California at Los Angeles, Los Angeles, California; and ²Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Cincinnati, Ohio

Submitted 27 July 2004 ; accepted in final form 28 September 2004

Cardiac protective signaling networks have been shown to involve PKC. However, the molecular mechanisms by which PKC interacts with other members of these networks to form task-specific modules remain unknown. Among 93 different PKC-associated proteins that have been identified, Akt and endothelial nitric oxide (NO) synthase (eNOS) are of importance because of their independent abilities to promote cell survival and prevent cell death. The simultaneous association of PKC, Akt, and eNOS has not been examined, and, in particular, the formation of a module containing these three proteins and the role of such a module in the regulation of NO production and cardiac protection are unknown. The present study was undertaken to determine whether these molecules form a signaling module and, thereby, play a collective role in cardiac signaling. Using recombinant proteins in vitro and PKC transgenic mouse hearts, we demonstrate the following: 1) PKC, Akt, and eNOS interact and form signaling modules in vitro and in the mouse heart. Activation of either PKC or Akt enhances the formation of PKC-Akt-eNOS signaling modules. 2) PKC directly phosphorylates and enhances activation of Akt in vitro, and PKC activation increases phosphorylation and activation of Akt in PKC transgenic mouse hearts. 3) PKC directly phosphorylates eNOS in vitro, and this phosphorylation enhances eNOS activity. Activation of PKC in vivo increased phosphorylation of eNOS at Ser¹¹⁷⁷, indicating eNOS activation. This study characterizes, for the first time, the physical, as well as functional, coupling of PKC, Akt, and eNOS in the heart and implicates these PKC-Akt-eNOS signaling modules as critical signaling elements during PKC-induced cardiac protection.

signaling network; protein-protein interactions; phosphorylation; cardioprotection; preconditioning; proteomics

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