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First published online October 27, 2004
doi: 10.1242/10.1242/jcs.01540

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The AMP-activated protein kinase pathway – new players upstream and downstream

Division of Molecular Physiology, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK

View larger version (13K): [in a new window]   Fig. 1. Physiological role of AMPK in the cell. Catabolism `charges up the battery' by converting ADP to ATP (bottom curved arrow) whereas ATP-consuming processes convert ATP to ADP (top curved arrow). If a cellular stress causes the rate of catabolism to fail to keep pace with the rate of ATP consumption, ADP levels will rise and ATP levels will fall. ADP is converted into AMP by adenylate kinase and this, combined with the fall in ATP, will activate AMPK. AMPK then promotes the restoration of energy balance by stimulating catabolism and inhibiting ATP-consuming processes.

View larger version (25K): [in a new window]   Fig. 2. Conserved domains in AMPK subunits: (A) subunits, (B) ß subunits and (C) subunits. The proposed function of each domain is indicated. The two isoforms of the (1, 2) and ß (ß1, ß2) subunits have very similar structures, but the three isoforms of the subunit (1, 2, 3) contain variable N-terminal regions of unknown function, and are drawn separately. [Redrawn from Hardie et al. (Hardie et al., 2003).]

View larger version (22K): [in a new window]   Fig. 3. Phylogenetic tree of the AMPK-related protein kinases. [Based on Manning et al. (Manning et al., 2002).]

View larger version (29K): [in a new window]   Fig. 4. Targets for AMPK. Target proteins and processes activated by AMPK activation are shown in green, and those inhibited by AMPK activation are shown in red. Where the effect is caused by a change in gene expression, an upward-pointing green arrow next to the protein indicates an increase, whereas a downward-pointing red arrow indicates a decrease in expression. Abbreviations: ACC1/ACC2, 1 () and 2 (ß) isoforms of acetyl-CoA carboxylase; CD36/FAT, CD36/fatty acid translocase; CFTR, cystic fibrosis transmembrane regulator; EF2, elongation factor-2; eNOS/nNOS. endothelial/neuronal isoforms of nitric oxide synthase; FAS, fatty acid synthase; G6Pase, glucose-6-phosphatase; GLUT1/4, glucose transporters; GS, glycogen synthase; HMGR, 3-hydroxy-3-methyl-CoA reductase; HSL, hormone-sensitive lipase; MEF2, myocyte-specific enhancer factor-2; NRF1, nuclear respiratory factor-1; PEPCK, phosphoenolpyruvate carboxykinase; PGC1, peroxisome proliferator-activated receptor- co-activator-1; TOR, mammalian target of rapamycin.

View larger version (15K): [in a new window]   Fig. 5. Regulation of protein synthesis and cell growth by AMPK and PKB/Akt by the mTOR pathway. Cellular stresses activate AMPK because the increase in AMP promotes its phosphorylation by LKB1; whereas growth factors activate PKB/Akt because the increase in phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] promotes its phosphorylation by PDK1. AMPK and PKB/Akt phosphorylate TSC2 at different sites, and this stimulates or inhibits, respectively, the ability of the TSC1-TSC2 complex to inhibit TOR. Amino acids also stimulate TOR through the TSC complex. TOR in turn stimulates protein synthesis, and hence cell growth, through ribosomal protein S6 kinase 1 (S6K1) and elongation factor-4E binding protein 1 (4E-BP1). The molecular events immediately upstream and downstream of TOR in this pathway are not shown in detail and remain incompletely understood.