Figure 2.

(A) Mechanisms of AKT regulation. The stimulation of receptor tyrosine kinases (RTKs) leads to activation of phosphatidylinositol 3-kinase (PI3K) and the subsequent conversion of the phosphatidylinositol (4,5)-bisphosphate (PI2P) into the phosphatidylinositol (3,4,5)-trisphosphate (PI3P). The inactive form of AKT (PH-in) is then recruited from the cytosol and translocated to the membrane thanks to the interaction between the AKT PH domain and PI3P. At this point, the double phosphorylation of AKT fully activates the protein (PH-out) that in turn modulates the downstream signaling proteins such as mammalian target of rapamycin (mTOR), IkappaB kinase (IKK), cAMP response element-binding protein (CREB) and Forkhead box O (FoxO). (B) AKT closed “PH-in” and opened “PH-out” conformations, with highlighted the three known ligand binding sites.