mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes. Metabolism Akt2 is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in increase of glycogen synthesis. GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Its role in HCV induced steatosis is unknown. Lysosomal biogenesis and autophagy Akt1 regulates TFEB, a master controller of lysosomal biogenesis, by direct phosphorylation at serine 467. Phosphorylated TFEB is excluded from the nucleus and less active. Pharmacological inhibition of Akt promotes nuclear translocation of TFEB, lysosomal biogenesis and autophagy. Angiogenesis Akt1 has also been implicated in angiogenesis and tumor development. Although deficiency of Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels. Clinical relevance Akt proteins are associated with tumor cell survival, proliferation, and invasiveness. The activation of Akt is also one of the most frequent alterations observed in human cancer and tumor cells. Tumor cells that have constantly active Akt may depend on Akt for survival. Therefore, understanding the Akt proteins and their pathways is important for the creation of better therapies to treat cancer and tumor cells. A mosaic-activating mutation (c. 49G→A, p.Glu17Lys) in Akt1 is associated with the Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other tissues. Akt inhibitors Akt inhibitors may treat cancers such as neuroblastoma. Some Akt inhibitors have undergone clinical trials. In 2007 VQD-002 had a phase I trial. In 2010 Perifosine reached phase II. but it failed phase III in 2012. Miltefosine is approved for leishmaniasis and under investigation for other indications including HIV. Akt1 is now thought to be the "key" for cell entry by HSV-1 and HSV-2 (herpes virus: oral and genital, respectively). Intracellular calcium release by the cell allows for entry by the herpes virus; the virus activates Akt1, which in turn causes the release of calcium. Treating the cells with Akt inhibitors before virus exposure leads to a significantly lower rate of infection. MK-2206 reported phase 1 results for advanced solid tumors in 2011, and subsequently has undergone numerous phase II studies for a wide variety of cancer types. In 2013 AZD5363 reported phase I results regarding solid tumors. with a study of AZD5363