Activation of cytosolic AMPK by phosphorylation

Stable Identifier
R-HSA-200421
Type
Reaction
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
11018120 Isoform-specific and exercise intensity-dependent activation of 5'-AMP-activated protein kinase in human skeletal muscle

Nielsen, P, Hansen, BF, Wojtaszewski, JF, Richter, EA, Kiens, B

J Physiol 2000
14985505 The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress

Bardeesy, N, Cantley, LC, Hurley, RL, Shaw, RJ, Witters, LA, Kosmatka, M, DePinho, RA

Proc Natl Acad Sci U S A 2004
14614828 LKB1 is the upstream kinase in the AMP-activated protein kinase cascade

Fryer, LG, Carlson, M, Leiper, FC, Carling, D, Neumann, D, Dickerson, K, Wallimann, T, Woods, A, Schlattner, U, Johnstone, SR

Curr Biol 2003
14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade

Alessi, DR, Hawley, SA, Reid, JL, Hardie, DG, Udd, L, Boudeau, J, Mäkelä, TP, Mustard, KJ

J Biol 2003
8779952 Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise

Hardie, DG, Winder, WW

Am J Physiol 1996
15579580 Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

Rubink, DS, Winder, WW

J Appl Physiol 2005
Participants
Participates
Catalyst Activity

protein serine/threonine kinase activity of LKB1:STRAD:MO25 [cytosol]

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Regulator
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