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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Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC.; ''The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.''; PubMedEurope PMCScholia
Davies SP, Helps NR, Cohen PT, Hardie DG.; ''5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC.''; PubMedEurope PMCScholia
Winder WW, Hardie DG.; ''Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise.''; PubMedEurope PMCScholia
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Hardie DG.; ''AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.''; PubMedEurope PMCScholia
Inoki K, Zhu T, Guan KL.; ''TSC2 mediates cellular energy response to control cell growth and survival.''; PubMedEurope PMCScholia
Rubink DS, Winder WW.; ''Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase.''; PubMedEurope PMCScholia
Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J.; ''Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.''; PubMedEurope PMCScholia
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The AMP-activated protein kinase (AMPK) is a highly conserved heterotrimeric kinase complex composed of a catalytic (alpha) subunit and two regulatory (beta and gamma) subunits. AMPK is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases, such as during nutrient deprivation or hypoxia (Hardie 2007). Upon energy stress, AMP directly binds to tandem repeats of cystathionine-beta-synthase (CBS) domains in the AMPK gamma subunit. Binding of AMP is thought to prevent dephosphorylation of the critical activation loop threonine in the alpha subunit (Hardie 2007). The phosphorylation of the activation loop threonine is absolutely required for AMPK activation. Biochemical and genetic analyses in worms, flies, and mice have revealed that the serine/threonine kinase STK11 (LKB1) represents the major kinase phosphorylating the AMPK activation loop under conditions of energy stress across metazoans (Sakamoto et al. 2005, Lee et al. 2007). LKB1 phosphorylates AMPK on Thr174 of the alpha 1 subunit (or Thr172 on the alpha 2 subunit) leading to activation of AMPK if the cellular AMP/ATP ratio is sufficiently high (Hawley et al. 2003, Woods et al. 2003, Shaw et al. 2004). Signals leading to this phosphorylation event can be mediated by exercise, leptin and adiponectin, the hypothalamic-sympathetic nervous system (SNS), and alpha adrenergic receptors, as demonstrated in studies of rat and human skeletal muscle (Minoksohi et al. 2002, Kahn et al. 2005).
Activated AMPK (phosphorylated on the alpha subunit and with AMP bound) phosphorylates TSC2 (also known as tuberin) on Ser-1387, thereby activating the GTPase activating protein (GAP) activity of the Tuberous Sclerosis Complex (TSC). The TSC tumor suppressor is a critical upstream inhibitor of the mTORC1 complex. TSC is a GTPase-activating protein that stimulates the intrinsic GTPase activity of the small G-protein Rheb. This inactivates Rheb by stimulating its GTPase activity. The GDP-bound form of Rheb looses the ability to activate the kinase activity of the mTORC1 complex (Sancak et al. 2007). Loss of TSC1 or TSC2 leads to hyperactivation of mTORC1.
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).
If AMP:ATP ratio rises, AMP (instead of ATP) is bound by the AMPK-gamma subunit, which inhibits the dephosphorylation of the AMPK-alpha subunit resulting in activation of AMPK. It is not clear, as of yet, whether AMP binds to unphosphorylated AMPK.
Upon complex formation with STRAD and MO25, LKB1 (also known as serine/threonine kinase 11, STK11) is mostly cytosolic. LKB1 attains 20x activity towards the substrates belonging to the subfamily of AMPK-like kinases (5'AMP-activated protein kinases).
TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of the small G-protein Rheb. This results in the conversion of Rheb:GTP to Rheb:GDP. GDP-bound Rheb is unable to activate mTOR (Inoki et al. 2003, Tee et al. 2003). It is not demonstrated that RHEB hydrolyzes GTP when present in the mTORC1 complex; given the low affinity of RHEB for mTOR, it may dissociate from the mTORC1 complex before TSC2 stimulates hydrolysis of GTP; TSC2 may not have access to critical residues of RHEB when present inside mTORC1.
Activated AMPK (phosphorylated on Thr172 or Thr174 and AMP bound) phosphorylates RPTOR (Raptor) on Ser722 and Ser792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn et al. 2008).
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with
p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTPAnnotated Interactions
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).
with
p-S722,S792-RPTOR:Ragulator:Rag:GNP:RHEB:GTP