Akt Activates the Mammalian Target of Rapamycin by Regulating Cellular ATP Level and AMPK Activity

Abstract

The serine/threonine kinase Akt is an upstream positive regulator of the mammalian target of rapamycin (mTOR). However, the mechanism by which Akt activates mTOR is not fully understood. The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR. Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), which is an activator of TSC2. We show that is Akt is a and a the phosphorylation of TSC2 and the inhibition of phosphorylation of TSC2 which mTOR. demonstrate that Akt upstream of and inhibition of TSC2 and of mTOR direct phosphorylation and by inhibition of phosphorylation of TSC2. We that the of mTOR by and inhibition of is the pathway by which Akt activates mTOR The serine/threonine kinase Akt is an upstream positive regulator of the mammalian target of rapamycin (mTOR). However, the mechanism by which Akt activates mTOR is not fully understood. The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR. Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), which is an activator of TSC2. We show that is Akt is a and a the phosphorylation of TSC2 and the inhibition of phosphorylation of TSC2 which mTOR. demonstrate that Akt upstream of and inhibition of TSC2 and of mTOR direct phosphorylation and by inhibition of phosphorylation of TSC2. We that the of mTOR by and inhibition of is the pathway by which Akt activates mTOR The serine/threonine protein kinase known protein kinase a of a of the mammalian target of rapamycin mammalian target of kinase tuberous sclerosis and AMP-activated protein mammalian target of kinase tuberous sclerosis and AMP-activated protein Akt which and by The Akt is the of the of Akt and the of Akt the Akt is by and by phosphorylation for of Akt and genetic show that Akt is a positive regulator of mTOR that the of mTOR by mTOR by and kinase and by and the which the phosphorylation of and of the is for mTOR mTOR is by the which is by protein TSC2 that tuberous sclerosis complex and mammalian and show that TSC2 is an upstream negative regulator of mTOR. 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