The phosphoinositide 3-kinase

The phosphoinositide 3-kinase (PI3K) pathway is widely implicated in carcinogenesis. In healthy cells, PI3K is recruited to the plasma membrane by the phosphorylated tyrosines of the RKTs or surrogate adapter proteins. Once recruited, PI3K drives the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), both entrenched in the inner leaflet of the plasma membrane. The formation of PIP3 in turn attracts the serine/threonine kinase AKT (also referred to as protein kinase B). Downstream signalling nodes from AKT vastly expand the functional repertoire of AKT. Accordingly, AKT has been subjected to tens of thousands studies in various fields of life sciences and medicine and well over 100 substrates for AKT have been described61. Three of the most well-established downstream targets from AKT are illustrated in Figure 4. All which are key signalling nodes integrating AKT signalling with other chief cellular signalling networks. GSK3 signals through several functionally diverse downstream targets involved in survival, proliferation, and metabolism. Most of them are degraded or inhibited in response to GSK3-mediated phosphorylation61. AKT exerts an inhibitory phosphorylation on GSK3 resulting in the upregulation of the downstream targets of GSK361. AKT further regulate the FoxO transcription factors by direct phosphorylation leading to the immediate translocation of FoxO transcription factors out of the nucleus and the coherent attenuation of their associated transcriptional programs. FoxO transcription factors target genes involved in cell cycle arrest, catabolism, growth inhibition and the induction of apoptosis. As such, AKT signalling promotes tumorigenesis by supressing the expression of these gene. Importantly, AKT also mediates the activation of the major signalling node mTORC1 that regulates a range of the metabolic adaptions underlying cell growth61. The mTORC1 complex governs the anabolic processes of lipid-, protein-, and nucleotide synthesis while negatively regulating the catabolic process of autophagy thereby sustaining tumour growth. AKT activates mTORC1 by relieving it from TSC2. Upon stimulation, AKT will deploy inhibitory phosphorylations on the five phosphorylation sites of TSC2 allowing for the activation of mTORC161