AMP-activated protein kinase (AMPK) signaling (WP1403)

AMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gamma-regulatory subunits. Humans and rodents have two alpha and beta and three gamma isoforms; some genes are subject to alternative splicing increasing the range of possible heterotrimer combinations. Cellular stresses that inhibit ATP production or increase its consumption change the AMP:ATP ratio and activate the pathway. AMPK activation by AMP is not completely understood; the current model states that binding of AMP to the gamma subunit leads to conformational changes that allosterically activate AMPK and render phosphorylated-Thr172 unavailable for inhibitory dephosphorylation. ATP antagonizes the effect of AMP; both AMP and ATP bind in a mutually exclusive manner to the Bateman (CBS) domains of the gamma subunit. The upstream kinase, known as Lkb1, is a complex of one catalytic and two regulatory subunits; Lkb1 is believed to be 'constitutively active'. In certain cell types, Thr172 can be phosphorylated by calmodulin-dependent protein kinase kinases (CAmKK), in turn activated by calcium. A well known role of AMPK is in the regulation of lipid metabolism; it stimulates fatty acids oxidation and inhibits their synthesis. Phosphorylation by AMPK inhibits acetyl-CoA carboxylase (ACC) and results in reduced levels of malonyl-CoA product. Malonyl CoA is a substrate in the de novo synthesis of fatty acids and fatty acids elongation. Importantly, it is also an inhibitor of the carnitine palmitoyl transferase I, required for the transfer of primed cytosolic fatty acids into the mitochondrion where they can undergo degradative beta-oxidation. AMPK inhibits mTOR signaling pathway by activating Tsc2 and downstream of Tsc2 by inhibiting Raptor component of mTOR complex 1 [note that this effect is opposite to Tsc2 phosphorylation and inactivation by PI3K-Akt signaling downstream of insulin]. AMPK is also involved in promoting glucose uptake and utilization and integrates adipokynes and hormonal signals in both the hypothalamus and the periphery with potential impact on energy expenditure and uptake by molecular mechanisms that remain to be established. Due to its roles in fuel regulation, the AMPK pathway is regarded as a potential therapeutic target for diabetes type II, obesity and metabolic syndrome. As a note, drugs used in the treatment of insulin resistance and diabetes can activate AMPK. AMP-activated protein kinase (AMPK) plays a key role as a master regulator of cellular energy homeostasis. The kinase is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia and heat shock. It exists as a heterotrimeric complex composed of a catalytic α subunit and regulatory β and γ subunits. Binding of AMP to the γ subunit allosterically activates the complex, making it a more attractive substrate for its major upstream AMPK kinase, LKB1. Several studies indicate that signaling through adiponectin, leptin and CAMKKβ may also be important in activating AMPK. As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies. For example, activation of AMPK enhances both the transcription and translocation of GLUT4, resulting in an increase in insulin-stimulated glucose uptake. In addition, it also stimulates catabolic processes such as fatty acid oxidation and glycolysis via inhibition of ACC and activation of PFK2. AMPK negatively regulates several proteins central to ATP consuming processes such as TORC2, glycogen synthase, SREBP-1 and TSC2, resulting in the downregulation or inhibition of gluconeogenesis, glycogen, lipid and protein synthesis. Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a key therapeutic target for the treatment of obesity, type II diabetes mellitus, and cancer. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1403 CPTAC Assay Portal]
last edited

Authors

Susan, Khanspers, Andra, MaintBot, Frances55, AdrienDefay, MartijnVanIersel, Christine Chichester, Jeangon, AlexanderPico, Mkutmon, Egonw, Zari, MirellaKalafati, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: adenosine monophosphate-activated protein kinase (AMPK) signaling pathway ATP biosynthetic pathway signaling pathway adenosine monophosphate-activated protein kinase (AMPK) signaling pathway

Participants

Label Type Compact Identifier
Metformin Metabolite cas:657-24-9
P53 GeneProduct ensembl:ENSG00000141510
HMG CoA Reductase GeneProduct ensembl:ENSG00000113161
ADRA1B GeneProduct ensembl:ENSG00000170214
Insulin GeneProduct ensembl:ENSG00000129965
HuR GeneProduct ensembl:ENSG00000066044
Cyclin A2 GeneProduct ensembl:ENSG00000145386
Cyclin A1 GeneProduct ensembl:ENSG00000133101
Glycolysis Pathway wikipathways:WP534
Glucose Metabolite hmdb:HMDB0000122
p21 GeneProduct ncbigene:1026
CCNB1 GeneProduct ensembl:ENSG00000134057
ADRA1A GeneProduct ensembl:ENSG00000120907
Akt2 GeneProduct ensembl:ENSG00000105221
p55-y GeneProduct ensembl:ENSG00000117461
CAMKK2 GeneProduct ensembl:ENSG00000110931
ADIPOR2 GeneProduct ensembl:ENSG00000006831
p70S6Ka GeneProduct ensembl:ENSG00000108443
4E-BP1 GeneProduct ncbigene:1978
AMPKy3 GeneProduct ncbigene:53632
GYS1(muscle) GeneProduct ensembl:ENSG00000104812
TSC2 GeneProduct ensembl:ENSG00000103197
AMPKa1 GeneProduct ncbigene:5562
Akt1 GeneProduct ensembl:ENSG00000142208
ACC1 GeneProduct ncbigene:31
Leptin GeneProduct ensembl:ENSG00000174697
SREBP1 GeneProduct ensembl:ENSG00000072310
cAMP Metabolite hmdb:HMDB0000058
INSR GeneProduct ensembl:ENSG00000171105
PI3K (III) GeneProduct ensembl:ENSG00000078142
AMPKy2 GeneProduct ncbigene:51422
mTOR GeneProduct ncbigene:2475
AMPKy1 GeneProduct ncbigene:5571
p85-a GeneProduct ensembl:ENSG00000145675
STRADA GeneProduct ensembl:ENSG00000266173
AMPKb2 GeneProduct ncbigene:5565
TSC1 GeneProduct ensembl:ENSG00000165699
p110-b GeneProduct ensembl:ENSG00000051382
p110-a GeneProduct ensembl:ENSG00000121879
STRADB GeneProduct ensembl:ENSG00000082146
ADIPOR1 GeneProduct ensembl:ENSG00000159346
PGC-1 GeneProduct ensembl:ENSG00000155846
HSL GeneProduct ensembl:ENSG00000079435
AMPKb1 GeneProduct ncbigene:5564
PLCB1 GeneProduct ensembl:ENSG00000182621
MEF2B GeneProduct ensembl:ENSG00000064489
eEF2K GeneProduct ensembl:ENSG00000103319
CPT1B (muscle) GeneProduct ncbigene:1375
GLUT4 GeneProduct ncbigene:6517
FA Synthase GeneProduct ensembl:ENSG00000169710
p70S6Kb GeneProduct ensembl:ENSG00000175634
CPT1A (liver) GeneProduct ncbigene:1374
Torc2 GeneProduct ncbigene:200186
ATP Metabolite hmdb:HMDB0001532
Calcium Metabolite hmdb:HMDB0000464
HNF4A GeneProduct ensembl:ENSG00000101076
LEPR GeneProduct ensembl:ENSG00000116678
PFK2 GeneProduct ncbigene:5209
p110-y GeneProduct ensembl:ENSG00000105851
AMP Metabolite hmdb:HMDB0003540
GEF GeneProduct ensembl:ENSG00000125520
GYS2 (liver) GeneProduct ensembl:ENSG00000111713
CAMKK1 GeneProduct ensembl:ENSG00000004660
LKB1 GeneProduct ensembl:ENSG00000118046
Malonyl-CoA Metabolite hmdb:HMDB0001175
eEF2 GeneProduct ncbigene:1938
MO25 GeneProduct ncbigene:51719
CPT1C (brain) GeneProduct ncbigene:126129
PRKACB GeneProduct ncbigene:5567
p110-d GeneProduct ensembl:ENSG00000171608
AMPKa2 GeneProduct ncbigene:5563
Raptor GeneProduct ncbigene:57521
p85-b GeneProduct ensembl:ENSG00000105647
Adiponectin GeneProduct ensembl:ENSG00000181092
PRKACG GeneProduct ncbigene:5568
ACC2 GeneProduct ncbigene:32
Gluconeogenesis Pathway wikipathways:WP534
Fatty Acid Oxidation Pathway wikipathways:WP143
GLUT4 GeneProduct ncbigene:6517
GLUT4 GeneProduct ncbigene:6517

References

  1. Carling D, Hardie DG. The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. Biochim Biophys Acta. 1989 Jun 15;1012(1):81–6. PubMed Europe PMC Scholia
  2. Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998 Feb 15;12(4):502–13. PubMed Europe PMC Scholia
  3. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000 Oct 19;10(20):1247–55. PubMed Europe PMC Scholia
  4. Hue L, Beauloye C, Marsin A-S, Bertrand L, Horman S, Rider MH. Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. J Mol Cell Cardiol. 2002 Sep;34(9):1091–7. PubMed Europe PMC Scholia
  5. Halse R, Fryer LGD, McCormack JG, Carling D, Yeaman SJ. Regulation of glycogen synthase by glucose and glycogen: a possible role for AMP-activated protein kinase. Diabetes. 2003 Jan;52(1):9–15. PubMed Europe PMC Scholia
  6. Hong YH, Varanasi US, Yang W, Leff T. AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem. 2003 Jul 25;278(30):27495–501. PubMed Europe PMC Scholia
  7. Inoki K, Zhu T, Guan K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577–90. PubMed Europe PMC Scholia
  8. Findlay GM, Harrington LS, Lamb RF. TSC1-2 tumour suppressor and regulation of mTOR signalling: linking cell growth and proliferation? Curr Opin Genet Dev. 2005 Feb;15(1):69–76. PubMed Europe PMC Scholia
  9. Hahn-Windgassen A, Nogueira V, Chen C-C, Skeen JE, Sonenberg N, Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem. 2005 Sep 16;280(37):32081–9. PubMed Europe PMC Scholia
  10. Holmes BF, Sparling DP, Olson AL, Winder WW, Dohm GL. Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase. Am J Physiol Endocrinol Metab. 2005 Dec;289(6):E1071-6. PubMed Europe PMC Scholia
  11. Lee WJ, Kim M, Park H-S, Kim HS, Jeon MJ, Oh KS, et al. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem Biophys Res Commun. 2006 Feb 3;340(1):291–5. PubMed Europe PMC Scholia
  12. Cheng A, Saltiel AR. More TORC for the gluconeogenic engine. Bioessays. 2006 Mar;28(3):231–4. PubMed Europe PMC Scholia
  13. Viana R, Aguado C, Esteban I, Moreno D, Viollet B, Knecht E, et al. Role of AMP-activated protein kinase in autophagy and proteasome function. Biochem Biophys Res Commun. 2008 May 9;369(3):964–8. PubMed Europe PMC Scholia
  14. Fu A, Screaton RA. Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family. Cell Cycle. 2008 Dec 15;7(24):3823–8. PubMed Europe PMC Scholia
  15. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf). 2009 May;196(1):65–80. PubMed Europe PMC Scholia
  16. Murgia M, Jensen TE, Cusinato M, Garcia M, Richter EA, Schiaffino S. Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle. J Physiol. 2009 Sep 1;587(Pt 17):4319–27. PubMed Europe PMC Scholia