Negative regulation of mTORC2 by glycogen synthase kinase-3β: an adaptive process to stress with an anticancer...

Exposure of cells to hormones, mitogens and growth factors can lead to the activation of PI3K and serine-threonine kinase Akt/PKB. Akt is recruited to the plasma membrane, a process that facilitates its phosphorylation at threonine 308 and serine (S)473 mediated by the PI3K-dependent kinase 1 and mTORC2 kinase, respectively. Active Akt has several targets, one of the most important being mTORC1, which is essential for stimulation of protein synthesis and cell growth. Active Akt phosphorylates the α- and β-isoforms of glycogen synthase kinase 3 (GSK-3), leading to the inhibition of GSK-3 activity and phosphorylation of proteins with key roles in cell proliferation and metabolism. Akt activity is induced in response to various forms of stress, mainly to facilitate cell survival and maintain cell proliferation. Recent work by Chen and colleagues has placed GSK-3β in a negative regulatory loop resulting in Akt inactivation. GSK-3β carries out this function via the phosphorylation of the mTORC2 component protein rictor at S1235, a modification that compromises the ability of mTORC2 to induce Akt activity by phosphorylation at S473. Rictor phosphorylation at S1235 can be detected in proliferating cells, but it can be particularly induced in cells exposed to endoplasmic reticulum stress. Rictor S1235 phosphorylation decreases the tumorigenic properties of activated Ras, providing evidence for a link between the GSK-3β-mTORC2 axis and tumorigenesis. A part of its potential role in regulating metabolic processes associated with endoplasmic reticulum stress, an interesting question is whether disruption of the GSK-3β-mTORC2 arm would have any implications in tumor formation and treatment.