AMP-activated protein kinase signaling (WP1403)
Homo sapiens
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]
Authors
Susan Coort , Kristina Hanspers , Andra Waagmeester , Frances , Adrien Defay , Martijn Van Iersel , Christine Chichester , Jean Gonzales , Alex Pico , Martina Summer-Kutmon , Egon Willighagen , Zahra Roudbari , Marianthi Kalafati , and Eric WeitzActivity
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Cited In
- Machine learning and bioinformatics to identify 8 autophagy-related biomarkers and construct gene regulatory networks in dilated cardiomyopathy (2022).
- Understanding signaling and metabolic paths using semantified and harmonized information about biological interactions (2022).
- CogNet: classification of gene expression data based on ranked active-subnetwork-oriented KEGG pathway enrichment analysis (2021).
- Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3 (2020).
- Systematic Assessment of Blood-Borne MicroRNAs Highlights Molecular Profiles of Endurance Sport and Carbohydrate Uptake (2019).
- Long Term Culture of the A549 Cancer Cell Line Promotes Multilamellar Body Formation and Differentiation towards an Alveolar Type II Pneumocyte Phenotype (2016).
- A network biology workflow to study transcriptomics data of the diabetic liver (2014).
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Organisms
Homo sapiensCommunities
Annotations
Pathway Ontology
ATP biosynthetic pathway adenosine monophosphate-activated protein kinase (AMPK) signaling pathway signaling pathway adenosine monophosphate-activated protein kinase (AMPK) signaling pathway| 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: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 | |
| 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 | |
| LEP | GeneProduct | ensembl:ENSG00000174697 | Leptin |
| SREBP1 | GeneProduct | ensembl:ENSG00000072310 | |
| 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 | |
| HNF4A | GeneProduct | ensembl:ENSG00000101076 | |
| LEPR | GeneProduct | ensembl:ENSG00000116678 | |
| PFK2 | GeneProduct | ncbigene:5209 | |
| p110-y | GeneProduct | ensembl:ENSG00000105851 | |
| GEF | GeneProduct | ensembl:ENSG00000125520 | |
| GYS2 (liver) | GeneProduct | ensembl:ENSG00000111713 | |
| CAMKK1 | GeneProduct | ensembl:ENSG00000004660 | |
| LKB1 | GeneProduct | ensembl:ENSG00000118046 | |
| 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 |
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- More TORC for the gluconeogenic engine. Cheng A, Saltiel AR. Bioessays. 2006 Mar;28(3):231–4. PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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