AMPK signaling (WP3154)

Bos taurus

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.

Authors

Martina Summer-Kutmon , Alex Pico , and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

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

Participants

Label Type Compact URI Comment
Metformin Metabolite cas:657-24-9
Glucose Metabolite hmdb:HMDB0000122
cAMP Metabolite hmdb:HMDB0000058
ATP Metabolite hmdb:HMDB0001532
Calcium Metabolite hmdb:HMDB0000464
AMP Metabolite hmdb:HMDB0003540
Malonyl-CoA Metabolite hmdb:HMDB0001175
TP53 GeneProduct ensembl:ENSBTAG00000001069 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000141510
HMGCR GeneProduct ensembl:ENSBTAG00000007840 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000113161
ADRA1B GeneProduct ensembl:ENSBTAG00000040253 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170214
INS GeneProduct ensembl:ENSBTAG00000013003 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000129965
ELAVL1 GeneProduct ensembl:ENSBTAG00000000613 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000066044
CCNA2 GeneProduct ensembl:ENSBTAG00000004943 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000145386
CCNA1 GeneProduct ensembl:ENSBTAG00000007284 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000133101
CDKN1A GeneProduct ensembl:ENSBTAG00000008353 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1026
CCNB1 GeneProduct ensembl:ENSBTAG00000014239 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000134057
ADRA1A GeneProduct ensembl:ENSBTAG00000031632 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000120907
AKT2 GeneProduct ensembl:ENSBTAG00000001400 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105221
PIK3R3 GeneProduct ensembl:ENSBTAG00000002979 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000117461
CAMKK2 GeneProduct ensembl:ENSBTAG00000010815 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000110931
ADIPOR2 GeneProduct ensembl:ENSBTAG00000009050 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000006831
RPS6KB1 GeneProduct ensembl:ENSBTAG00000016851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000108443
EIF4EBP1 GeneProduct ensembl:ENSBTAG00000027654 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1978
PRKAG3 GeneProduct ensembl:ENSBTAG00000013492 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:53632
GYS1 GeneProduct ensembl:ENSBTAG00000039958 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000104812
TSC2 GeneProduct ensembl:ENSBTAG00000020617 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000103197
PRKAA1 GeneProduct ensembl:ENSBTAG00000000013 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5562
AKT1 GeneProduct ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000142208
OB GeneProduct ensembl:ENSBTAG00000014911 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000174697
SREBF1 GeneProduct ensembl:ENSBTAG00000007884 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000072310
IR-A GeneProduct ensembl:ENSBTAG00000012687 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171105
PIK3C3 GeneProduct ensembl:ENSBTAG00000026290 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000078142
PRKAG2 GeneProduct ensembl:ENSBTAG00000002917 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51422
MTOR GeneProduct ensembl:ENSBTAG00000015325 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2475
PRKAG1 GeneProduct ensembl:ENSBTAG00000014426 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5571
PIK3R1 GeneProduct ensembl:ENSBTAG00000010989 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000145675
STRADA GeneProduct ensembl:ENSBTAG00000000056 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000266173
PRKAB2 GeneProduct ensembl:ENSBTAG00000014387 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5565
TSC1 GeneProduct ensembl:ENSBTAG00000005190 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000165699
PIK3CB GeneProduct ensembl:ENSBTAG00000006909 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000051382
PIK3CA GeneProduct ensembl:ENSBTAG00000009232 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000121879
STRADB GeneProduct ensembl:ENSBTAG00000019298 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000082146
ADIPOR1 GeneProduct ensembl:ENSBTAG00000009727 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000159346
PPARGC1B GeneProduct ensembl:ENSBTAG00000012943 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000155846
HSL GeneProduct ensembl:ENSBTAG00000038321 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000079435
PRKAB1 GeneProduct ensembl:ENSBTAG00000005940 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5564
PLCB1 GeneProduct ensembl:ENSBTAG00000008338 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000182621
EEF2K GeneProduct ensembl:ENSBTAG00000017662 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000103319
CPT1B GeneProduct ensembl:ENSBTAG00000016048 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1375
SLC2A4 GeneProduct ensembl:ENSBTAG00000009190 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6517
FASN GeneProduct ensembl:ENSBTAG00000015980 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169710
RPS6KB2 GeneProduct ensembl:ENSBTAG00000009175 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000175634
CPT1A GeneProduct ensembl:ENSBTAG00000021999 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1374
Torc2 GeneProduct ensembl:ENSBTAG00000047190 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:200186
HNF4A GeneProduct ensembl:ENSBTAG00000012116 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000101076
OB-R GeneProduct ensembl:ENSBTAG00000005910 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000116678
PFKFB3 GeneProduct ensembl:ENSBTAG00000008401 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5209
PIK3CG GeneProduct ensembl:ENSBTAG00000020848 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105851
SLC2A4RG GeneProduct ensembl:ENSBTAG00000016664 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000125520
GYS2 GeneProduct ensembl:ENSBTAG00000013333 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000111713
CAMKK1 GeneProduct ensembl:ENSBTAG00000007166 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000004660
STK11 GeneProduct ensembl:ENSBTAG00000011639 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000118046
EEF2 GeneProduct ensembl:ENSBTAG00000004258 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1938
CAB39 GeneProduct ensembl:ENSBTAG00000040055 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51719
CPT1C GeneProduct ensembl:ENSBTAG00000012205 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:126129
PRKACB GeneProduct ensembl:ENSBTAG00000011953 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5567
PIK3CD GeneProduct ensembl:ENSBTAG00000018984 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171608
PRKAA2 GeneProduct ensembl:ENSBTAG00000018747 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5563
RPTOR GeneProduct ensembl:ENSBTAG00000002883 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:57521
PIK3R2 GeneProduct ensembl:ENSBTAG00000002350 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105647
ADIPOQ GeneProduct ensembl:ENSBTAG00000019813 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000181092
ACACB GeneProduct ensembl:ENSBTAG00000022058 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:32

References

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