Myocardial AKT: the omnipresent nexus

Abstract

One of the greatest examples of integrated signal transduction is revealed by examination of effects mediated by AKT kinase in myocardial biology. Positioned at the intersection of multiple afferent and efferent signals, AKT exemplifies a molecular sensing node that coordinates dynamic responses of the cell in literally every aspect of biological responses. The balanced and nuanced nature of homeostatic signaling is particularly essential within the myocardial context, where regulation of survival, energy production, contractility, and response to pathological stress all flow through the nexus of AKT activation or repression. Equally important, the loss of regulated AKT activity is primarily the cause or consequence of pathological conditions leading to remodeling of the heart and eventual decompensation. This review presents an overview compendium of the complex world of myocardial AKT biology gleaned from more than a decade of research. Summarization of the widespread influence that AKT exerts upon myocardial responses leaves no doubt that the participation of AKT in molecular signaling will need to be reckoned with as a seemingly omnipresent regulator of myocardial molecular biological responses.

FIGURE 1

Upstream AKT signaling. Schematic diagram representing the receptor-mediated phosphorylation and activation steps required for the ultimate phosphorylation and activation of AKT. GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; IRS-1, insulin receptor substrate 1; PI3K, phosphoinositide 3-kinase; PDK1, phosphoinositide-dependent protein kinase-1, PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; PH, plekstrin homology.

FIGURE 2

Pathways of AKT influencing the mTOR protein complexes. Schematic diagram representing the regulatory functions of the mTORC1 and mTORC2 complexes in relation to AKT signaling and cellular outcomes. Induction of AKT activity by extracellular signals results in the activation of mTORC1. mTORC2 activity positively regulates AKT activity. Green arrows represent positive regulation. Green arrows leading to phosphorylation represent activation via phosphorylation. Red arrows represent negative regulation. Red arrows leading to phosphorylation represent repression via phosphorylation.

FIGURE 3

Schematic overview of selected AKT targets, many of which are highlighted in this review. Cellular signaling around AKT and AKT substrates regulates major cellular processes in the myocardium. Activated AKT increases protein translation, cellular growth, metabolism, and cell cycle activity through regulation of downstream mediators.