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Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2005, PMID: 16027121

Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity.

Hahn-Windgassen, Annett; Nogueira, Veronique; Chen, Chia-Chen; Skeen, Jennifer E; Sonenberg, Nahum; Hay, Nissim

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 in Akt1/Akt2 DKO cells AMP/ATP ratio is markedly elevated with concomitant increase in AMPK activity, whereas in cells expressing activated Akt there is a dramatic decrease in AMP/ATP ratio and a decline in AMPK activity. Currently, the Akt-mediated phosphorylation of TSC2 and the inhibition of AMPK-mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR. Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK-mediated phosphorylation of TSC2. We propose that the activation of mTOR by Akt-mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo.

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Text Mining Data

mammalian target of rapamycin → Akt: " Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity "

mTOR → Akt: " However, the mechanism by which Akt activates mTOR is not fully understood "

mTOR → Akt: " 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 "

TSC2 ⊣ Akt: " Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR "

mTOR → Akt: " Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR "

TSC2 ⊣ Akt: " Currently, the Akt mediated phosphorylation of TSC2 and the inhibition of AMPK mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR "

TSC2 → AMPK: " Currently, the Akt mediated phosphorylation of TSC2 and the inhibition of AMPK mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR "

TSC2 ⊣ Akt: " Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 "

TSC2 → mTOR: " Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 "

TSC2 → AMPK: " Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 "

Akt → mTOR: " Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 "

mTOR → Akt: " We propose that the activation of mTOR by Akt mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo "

Manually curated Databases

In total, 35 gene pairs are associated to this article in curated databases