Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

Abstract

Phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) constitute the core components of the PI3K/AKT/mTOR signalling cascade, regulating cell proliferation, survival and metabolism. Although these functions are well-defined in the context of tumorigenesis, recent studies -in particular those using pluripotent stem cells -have highlighted the importance of this pathway to development and cellular differentiation. Here, we review the recent in vitro and in vivo evidence for the role PI3K/AKT/mTOR signalling plays in the control of pluripotency and differentiation, with a particular focus on the molecular mechanisms underlying these functions.

Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

“…The PI3K-AKT signaling pathway comprehensively regulates cell survival, proliferation, metabolism, and stemness1011. Its acute activation in normal stem cells can lead to senescence or depletion of the stem cell pool2526, suggesting that it is tightly regulated in stem cell homeostasis.…”

“…It can phosphorylate a number of key chromatin-modifying enzymes, such as the histone acetyltransferase p300, the DNA methyltransferase DNMT1, the H3K27 methyltransferase EZH2, and the histone ubiquitylating enzyme BMI1, altering the function of these enzymes9. Besides its well established roles in anti-apoptosis and cell survival, emerging evidence indicated that AKT is also a key player in stemness regulation and CSC biology, and thus a promising target for developing anticancer drugs against CSCs1011. OCT4, a master transcription factor controlling stem cell self-renewal and pluripotency, is considered as one of the most important mediators for cancer epigenetics8.…”

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

“…Given that cellular metabolic processes are critical for the programming of stem cells (9)(10)(11), it raises the potential that maternal factors present in the OB intrauterine environment that affect energy regulation or differentiation may have significant impacts on the long-term programming and function of these cells, which exist in bone, muscle, and mature adipose tissue.…”

Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases

“…PI3K-Akt-mTOR cues regulate various cellular functions, including nutrient uptake, cell proliferation, growth, autophagy, apoptosis, and migration (Hennessy et al 2005; Yu & Cui 2016). In the absence of extracellular stimulators, Akt is cytoplasmic and inactive (Alessi et al 1996).…”