Energy dependent regulation of mTOR by LKB1-AMPK

European Bioinformatics Institute, New York University Langone Medical Center, Ontario Institute for Cancer Research, Oregon Health and Science University. The contents of this document may be freely copied and distributed in any media, provided the authors, plus the institutions, are credited, as stated under the terms of Creative Commons Attribution 4.0 International (CC BY 4.0) License. For more information see our license. This is just an excerpt of a full-length report for this pathway. To access the complete report, please download it at the Reactome Textbook. 14/11/2022


Introduction
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Literature references
Baas, AF., Boudeau, J., Sapkota, GP., Smit, L., Medema, R., Morrice, NA. et al. (2003).Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.phorylates 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).
Preceded by: LKB1 forms a trimeric complex with STRAD and MO25 Followed by: Phosphorylated AMPK binds AMP, AMPK is dephosphorylated

Table of Contents
The development of Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), University of Toronto (CFREF Medicine by Design), European Union (EU STRP, EMI-CD), and the European Molecular Biology Laboratory (EBI Industry program).

LKB1 forms a trimeric
complex with STRAD and MO25 ↗ Location: Energy dependent regulation of mTOR by LKB1-AMPK Stable identifier: R-HSA-380942 Type: binding Compartments: cytosol 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).
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 phos-