The Akt kinases: isoform specificity in metabolism and cancer

Abstract

The Akt (PKB) protein kinases are critical regulators of human physiology that control an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The Akt kinase family is comprised of three highly homologous isoforms: Akt1 (PKBalpha), Akt2 (PKBbeta) and Akt3 (PKBgamma). Phenotypic analyses of Akt isoform knockout mice documented Akt isoform specific functions in the regulation of cellular growth, glucose homeostasis and neuronal development. Those studies establish that the functions of the different Akt kinases are not completely overlapping and that isoform-specific signaling contributes to the diversity of Akt activities. However, despite these important advances, a thorough understanding about the specific roles of Akt family members and the molecular mechanisms that determine Akt isoform functional specificity will be essential to elucidate the complexity of Akt regulated cellular processes and how Akt isoform-specific deregulation might contribute to disease states. Here, we summarize recent advances in understanding the roles of Akt isoforms in the regulation of metabolism and cancer, and possible mechanisms contributing to Akt isoform functional specificity.

Figure 1

Regulation of Akt signaling. A. Growth factor-mediated Akt activation. In response to numerous growth factors and cytokines Akt is activated downstream of PI3-kinase following a multistep mechanism. Activated PI3-kinase converts PIP2 into PIP3 providing sites of recruitment at the plasma membrane of proteins containing PH domains, including Akt and PDK1 kinases. Upon translocation to the plasma membrane Akt is phosphorylated by PDK1 within the catalytic domain and mTORC2 within the hydrophobic motif, which renders Akt catalytically active. Activated Akt, trough the phosphorylation of numerous downstream targets located throughout the cell, regulates a wide array of cellular functions. B. Overlapping and specific functions of the Akt family members. Summarized are common and distinct Akt isoform functions elucidated from the phenotypic analysis of single and double Akt isoform knockout mice. C. Potential mechanisms dictating Akt isoform functional specificity.

Figure 2

Akt2 signaling specificity in insulin-mediated glucose uptake. Insulin binding to the insulin receptor at the surface of adipocytes leads the activation and the autophosphorylation of the receptor, followed by recruitment and phosphorylation of insulin receptor substrate proteins (IRS). Phosphorylated IRS create docking sites for the recruitment of PI3-kinase which converts PIP2 into PIP3, providing sites for the recruitment of Akt kinases to the plasma membrane. Both Akt1 and Akt2 translocate to the plasma membrane in response to PI3-kinase activation and both kinases are activated by phosphorylation trough PDK1 and the mTORC2. Using Akt1 and Akt2 reporters and total internal reflection fluorescence (TIRF) microscopy we found that upon insulin stimulation Akt2 accumulates at the plasma membrane environment (TIRF zone) to a larger degree than Akt1. This distinct subcellular distribution facilitates Akt2 phosphorylation and inactivation of the Rab GAP AS160 possibly located on GLUT4 containing vesicles. Inactivation of AS160 allows the subsequent docking and fusion of GLUT4 vesicles with the plasma, and consequently the entrance of glucose into the cells.