Though mutation of Akt itself is rare, Carpten et al. recently described somatic mutations occurring inside the PH domain of Akt in a little percentage of human breast, ovarian, and colorectal cancers . Downstream substrates of activated Akt Akt recognizes and phosphorylates the consensus sequence RXRXX when surrounded by hydrophobic residues. Since this sequence is present in numerous proteins, a number of Akt substrates have already been identified and validated . These substrates handle essential cellular processes such as apoptosis, cell cycle progression, transcription, and translation. For example, Akt phosphorylates the FoxO subfamily of forkhead loved ones transcription components, which inhibits transcription of numerous pro apoptotic genes, e.g Fas L, IGFBP and Bim . Moreover, Akt can straight regulate apoptosis by phosphorylating and inactivating pro apoptotic proteins just like Terrible, which controls release of cytochrome c from mitochondria, and ASK , a mitogen activated protein kinase kinase involved in strain and cytokine induced cell death . In contrast, Akt can phosphorylate IKK, which indirectly increases the activity of nuclear issue kappa B and stimulates the transcription of pro survival genes .
Cell cycle progression can also be effected by Akt by means of its inhibitory phosphorylation in the cyclin dependent kinase inhibitors, pWAF CIP and pKIP , and inhibition of GSK by Akt stimulates cell cycle progression by stabilizing cyclin D expression . Recently, a novel pro survival Akt substrate, PRAS , has been described , whereby phosphorylation SP600125 of PRAS by Akt attenuates its potential to inhibit mTORC kinase activity. It has been recommended that PRAS might be a distinct substrate of Akt . As a result, Akt inhibition may have pleiotropic effects on cancer cells that could contribute to an antitumor response. The best studied downstream substrate of Akt could be the serine threonine kinase mTOR . Akt can directly phosphorylate and activate mTOR, also as result in indirect activation of mTOR by phosphorylating and inactivating TSC , which normally inhibits mTOR through the GTP binding protein Rheb .WhenTSCis inactivated by phosphorylation, the GTPase Rheb is maintained in its GTP bound state, permitting for enhanced activation of mTOR.
mTOR exists in two complexes: the TORC complex, in which mTOR is bound to Raptor, plus the TORC complex, in which mTOR is Celastrol bound to Rictor. Inside the TORC complex, mTOR signals to its downstream effectors S kinase ribosomal protein S and EBP eIFE to handle protein translation. While mTOR is in general regarded as a downstream substrate of Akt,mTORcan also phosphorylate Akt when bound to Rictor in TORC complexes, probably supplying a level of positive feedback on the pathway . Finally, the downstream mTOR effector S kinase may also regulate the pathway by catalyzing an inhibitory phosphorylation on insulin receptor substrate proteins.