fig1

Figure 1. Overview of PI3K/AKT/mTOR signaling pathway. Activation (blue arrows) of growth factor (GF) receptor tyrosine kinase (RTK), resulting in autophosphorylation on tyrosine residues, recruits Phosphatidyl-inositol-3-kinase (PI3K) to the cell membrane. Direct binding of PI3K to the tyrosine residues causes activation via the PI3K catalytic subunit^[42]. Activated PI3K in turn phosphorylates secondary messenger phosphatidylinositol-3,4,5-bisphospate (PIP2) which converts to phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 is responsible for the recruitment of the protein kinase AKT to the cell surface where its subsequent activation/inhibition by multiple molecules leads to involvement in numerous downstream signaling pathways^[43,44]. AKT is activated via phosphorylation at two key residues: S473 and T308^[40]. Protein serine/threonine kinase-3’-PDK1 and PDK2, recruited to and activated at the cell surface are responsible for activating AKT, along with protein kinases ATM and ATR, and HSP90. DNA-PK, a nuclear serine/threonine kinase essential for non-homologous end-joining (NHEJ) repair, activates AKT via phosphorylation at S473 in response to cisplatin-induced DNA damage in platinum resistant EOC cells^[19]. PTEN, tuberous sclerosis protein 1 (TSC1) and TSC2 are the main negative regulators (yellow arrows) of the pathway, with phosphorylation of TSC2 by AKT releasing the inhibitory effect on mTORC1 via the GTP-binding protein Rheb^[42]. mTORC1 activates p70S6K and inhibits 4E-BP1, resulting in protein synthesis and cell growth, and mTORC2 activates AKT itself; overall mTOR activation leads to cell growth and survival. Inactivation of pro-apoptotic molecules YAP, Procaspase 9 (Casp9) and BAD, as well as inhibiting Forkhead transcription factors [e.g., Forkhead box protein O1 (FoxO1)] result in increased cell survival^[45,46]. AKT is an essential part of the insulin signaling pathway. Activated in response to insulin stimulation, AKT causes Glucose Transporter 4 (GLUT4) to translocate to the cell surface, facilitating glucose uptake. Additionally, the inhibition of glycogen synthase kinase 3 beta (GSK-3β) by AKT increases glycogen production^[47]. The role of AKT in glucose metabolism is again apparent through its inhibition of FoxO1, which suppresses hepatic glucose production^[48]. The PI3K/AKT/mTOR signaling pathway includes points of cross-regulation and communication with other common signaling pathways, e.g., JNK and RAS-ERK. The AKT substrate c-RAF is activated by RAS and initiates a kinase cascade leading to ERK activation^[49]. The phosphorylation of c-RAF by AKT inhibits its activity and subsequent downstream activity in the RAS/RAF/MEK/ERK signaling cascade known for its role in apoptosis and cell differentiation^[50]. AKT involvement with the JNK pathway, a stress- and nutrient-response pathway, directly modifies activation of target genes, many of which are involved in adaptations to extra-cellular stresses^[51].