Akt as a therapeutic target in cancer

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…12,16 In the presence of abundant growth factors and nutrients, there is an increase in phosphorylation and activation of molecules crucial to protein translation. 18,19 Conversely, phosphorylation can be decreased during times of environmental stress, nutrient deficiency, and even in the presence of viruses. 13 mTOR exists in two different complexes: mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2).…”

“…[3][4][5] PIP3 subsequently binds to the pleckstrin homology domain of Akt1 kinase (also known as protein kinase B) to recruit Akt1 to the cell membrane for phosphorylation. 19,24 Akt1 is phosphorylated at Threonine 308 by phosphoinositide-dependent protein kinase 1 (PDK-1) [25][26][27] and at Serine 473 (Ser473) by PDK-2, which is believed to be rictor. 9,14,19,27 Activated Akt1 inactivates the tuberous sclerosis complex (TSC) composed of TSC1 and TSC2, by directly phosphorylating the GTPase-activating protein TSC2.…”

“…19,24 Akt1 is phosphorylated at Threonine 308 by phosphoinositide-dependent protein kinase 1 (PDK-1) [25][26][27] and at Serine 473 (Ser473) by PDK-2, which is believed to be rictor. 9,14,19,27 Activated Akt1 inactivates the tuberous sclerosis complex (TSC) composed of TSC1 and TSC2, by directly phosphorylating the GTPase-activating protein TSC2. TSC2 and TSC1 normally act together as tumor-suppressor proteins inhibiting cell growth by negatively regulating the small GTPase-activating protein Ras homolog enriched in brain (Rheb).…”

“…14 When released from TSC inhibition, Rheb is free to activate mTORC1. 19,22,28 Activated mTOR can subsequently phosphorylate p70 S6 kinase-1 (p70 S6K) and 4E-BP. p70 S6K, a serine/threonine kinase, phosphorylates the ribosomal protein S6 of the 40S ribosomal subunit at Ser235 and 236 to increase translation of 5 0 terminal oligopyrimidine tract mRNAs 10 and also binds to mitochondrial membranes and inactivates the pro-apoptotic molecule BAD.…”

“…For example, studies have found that treatment with the mTOR inhibitor rapamycin actually results in increased Akt activation and eIF4E phosphorylation. 34 mTORC1 and p70 S6K are part of a negative feedback loop with PI3K/Akt, 19,22 controlling the response of PI3K to insulin through insulin receptor substrate (IRS) proteins. IRS-1 is normally phosphorylated and activated by p70 S6K.…”