The Paradox of Akt-mTOR Interactions

Abstract

The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review “PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle” we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.

Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

“…However, activation of p-Akt via mTOR2 signaling cascades is also involved in regulation of p-Akt (S473). Additionally, inhibition of mTOR1 by rapamycin derivatives increases mTOR2, resulting in activation of p-Akt (S473) (Sarbassov et al 2005;McDonald et al 2008;Breuleux et al 2009;Vadlakonda et al 2013). In line with this notion, attenuation of PTS noise-induced hearing loss with rapamycin may also be due in part to the activation of p-Akt (S473) (Yuan et al 2014, submitted).…”

Diamond, graphite, and graphene oxide nanoparticles decrease migration and invasiveness in glioblastoma cell lines by impairing extracellular adhesion

“…The suppression of mTORC1 leads to stimulation of mTORC2, which positively regulates cell survival and proliferation at different signaling levels, mainly by the activation of AKT. 54 Apart from inhibition of EGFR phosphorylation, a decrease in the activation of mTOR could be caused by profound endocytosis of nanoparticles. Reports have shown that mTORC1 activation can be decreased during the failure of lysosome reformation.…”

PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update

“…Cell cycle progression is regulated by Akt through indirect stabilization of cyclin D1 and Myc. Akt also stimulates protein synthesis and cell growth by activating the mammalian target of rapamycin (mTOR) pathway through the inhibition of the heterotrimeric complex consisting of tuberous sclerosis 1 or hamartin (TSC1) and tuberous sclerosis 2 or tuberin (TSC2) (Manning & Cantley 2007, Vadlakonda et al 2013.…”