Energy dependent regulation of mTOR by LKB1-AMPK (Homo sapiens)
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Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. This phosphorylation is immediately removed in basal conditions by PP2C, but if the cellular AMP:ATP ratio rises, this activation is maintained, as AMP binding by AMPK inhibits the dephosphorylation. AMPK then activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway.
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Phosphorylation of TSC1 and TSC2 serves as an integration point for a wide variety of environmental signals that regulate mTORC1 (Sabatini 2006). Mitogen-activated kinases including Akt, Erk, and Rsk directly phosphorylate TSC2, leading to its inactivation by an unknown mechanism. Another Akt substrate, PRAS40, was recently shown to bind and inhibit the mTORC1 complex. Upon phosphorylation by Akt, PRAS40 no longer inhibits mTORC1 (Sancak et al. 2007; Vander Haar et al. 2007).