Journal Club of the Week: Role of Phosphoinositide 3-Kinase (PI3K) inhibitors and signaling pathway

In the 12th December 2016, journal club meeting, PI3K/Akt/Mtor pathway was discussed. It was described that PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating Ptdlns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. The pathway is antagonized by various factors including PTEN, GSK3B, and HB-9. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, neural stem cells specifically. It is the difficulty in finding an appropriate amount of proliferation versus differentiation that researchers are trying to determine in order to utilize this balance in the development of various therapies. Additionally, this pathway has been found to be a necessary component in neural long term potentiation.
The signaling activates the PI3K/AKT pathway which works to promote proliferation. In this way, when there is high glucose and abundant energy in the organism, the PI3K/AKT pathway is activated and NSCs tend to proliferate. When there are low amounts of available energy, the PI3K/AKT pathway is less active and cells adopt a quiescent state. This occurs, in part, when AKT phosphorylates FOXO, keeping FOXO in the cytoplasm. This directly leads to the docking of AMPA in the post synapse. mTOR activated p7056K and inactivated 4EBP1 which changes gene expression to allow LTP to occur. Long-term fear conditioning training was affected in rats but there was no effect in short term conditioning. Specifically, amygdala fear conditioning was lost. This is a type of trace conditioning which is a form of learning that requires association of a conditioned stimulus with an unconditioned stimulus. This effect was lost in PI3K knockdowns and increased in PI3K over-expressions.