AMP-activated protein kinase signaling (Homo sapiens)

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Metformin4, 113, 79, 10151, 126, 161481352Glycogen synthesisHepatic fatty acidand VLDL synthesisBrainSterol / isoprenoidsynthesisAMP kinase/Expression ofmitochondrialgenes in musclePI3 kinaseLow glucose,hypoxia, ischemia,heat shockP53HMG CoA reductaseADRA1BInsulinHuRCyclin A2Cyclin A1GlycolysisGlucosep21CCNB1ADRA1AAkt2p55-yCAMKK2ADIPOR2p70S6Ka4E-BP1AMPKy3GYS1 (muscle)TSC2AMPKa1Akt1ACC1LeptinSREBP1cAMPINSRPI3K (III)AMPKy2mTORAMPKy1p85-aSTRADAAMPKb2TSC1p110-b p110-aSTRADBADIPOR1PGC-1HSLAMPKb1PLCB1MEF2BeEF2KCPT1B (muscle)GLUT4FA Synthasep70S6KbCPT1A (liver)Torc2ATPCalciumHNF4ALEPRPFK2p110-yAMPGEFGYS2 (liver)CAMKK1LKB1Malonyl-CoAeEF2MO25CPT1C (brain)PRKACBp110-dAMPKa2Raptorp85-bAdiponectinPRKACGACC2GLUT4 vesicleLipolysisProtein synthesisGluconeogenesisFatty acid oxidationGLUT4GLUT4


Description

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 CPTAC Assay Portal

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Bibliography

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  1. Hue L, Beauloye C, Marsin AS, 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 PubMed Europe PMC Scholia
  2. Shaw RJ; ''LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.''; Acta Physiol (Oxf), 2009 PubMed Europe PMC Scholia
  3. Halse R, Fryer LG, McCormack JG, Carling D, Yeaman SJ; ''Regulation of glycogen synthase by glucose and glycogen: a possible role for AMP-activated protein kinase.''; Diabetes, 2003 PubMed Europe PMC Scholia
  4. 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 PubMed Europe PMC Scholia
  5. Viana R, Aguado C, Esteban I, Moreno D, Viollet B, Knecht E, Sanz P; ''Role of AMP-activated protein kinase in autophagy and proteasome function.''; Biochem Biophys Res Commun, 2008 PubMed Europe PMC Scholia
  6. 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 PubMed Europe PMC Scholia
  7. 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 PubMed Europe PMC Scholia
  8. 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 PubMed Europe PMC Scholia
  9. Cheng A, Saltiel AR; ''More TORC for the gluconeogenic engine.''; Bioessays, 2006 PubMed Europe PMC Scholia
  10. Fu A, Screaton RA; ''Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family.''; Cell Cycle, 2008 PubMed Europe PMC Scholia
  11. 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 PubMed Europe PMC Scholia
  12. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L; ''Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.''; Curr Biol, 2000 PubMed Europe PMC Scholia
  13. 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 PubMed Europe PMC Scholia
  14. Hahn-Windgassen A, Nogueira V, Chen CC, 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 PubMed Europe PMC Scholia
  15. Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M, Lee KU, Park JY; ''AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1.''; Biochem Biophys Res Commun, 2006 PubMed Europe PMC Scholia
  16. Inoki K, Zhu T, Guan KL; ''TSC2 mediates cellular energy response to control cell growth and survival.''; Cell, 2003 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
128119view13:08, 27 January 2024EweitzFix typos, refine layout, standardize case
126272view16:20, 19 April 2023EgonwLicense is CCZero
123620view08:20, 7 August 2022EgonwModified title
121114view07:59, 9 February 2022EgonwMade three pathways clickable
116516view10:54, 7 May 2021EweitzModified title
106688view13:00, 17 September 2019MaintBotHMDB identifier normalization
105868view23:29, 15 August 2019KhanspersModified description
105428view04:29, 8 August 2019KhanspersModified description
105427view04:28, 8 August 2019KhanspersModified description
98156view17:59, 27 July 2018AlexanderPicoOntology Term : 'signaling pathway' added !
90259view20:18, 27 October 2016AlexanderPicoupdated vesicle and pathway node glyphs
90018view19:27, 8 October 2016AlexanderPicoModified description
89800view11:29, 6 October 2016Mkutmonfixed special characters in description
86073view08:47, 29 June 2016MirellaKalafatiModified title
79471view11:56, 23 March 2015ZariChanded ID for STRADA gene
78804view09:11, 31 January 2015EgonwConnected dots.
75220view21:45, 9 May 2014Khanspersconnected interactions
73193view10:42, 10 January 2014Mkutmonupdated layout
71709view20:01, 17 October 2013MaintBotremoved data source from nodes without identifier
69892view19:03, 11 July 2013AlexanderPicoModified title
68209view00:52, 2 July 2013JeangonPeriodical save, work in progress
67040view09:58, 26 June 2013Christine ChichesterOntology Term : 'adenosine monophosphate-activated protein kinase (AMPK) signaling pathway' added !
63159view20:18, 8 May 2013MaintBotUpdating GPML version
60818view17:38, 28 March 2013MaintBotOntology Term : 'ATP biosynthetic pathway' added !
59114view22:25, 21 February 2013MaintBotUpdated Ensembl data source
44950view12:34, 6 October 2011MartijnVanIerselOntology Term : 'AMPK signaling pathway' added !
43615view14:06, 8 July 2011AdrienDefayadd DATABASE name for some Pathway Link
42309view17:22, 16 March 2011KhanspersReverted to version '23:18, 1 March 2011' by Khanspers
42306view16:01, 15 March 2011Frances55muscle growth
41064view23:18, 1 March 2011MaintBotRemoved redundant pathway information and comments
38943view22:54, 24 September 2010KhanspersSpecify description
33370view14:34, 30 November 2009MaintBotRemoved group label
33329view12:12, 24 November 2009AndraRemoved reference
33328view11:55, 24 November 2009AndraAdd reference
33179view17:41, 5 November 2009KhanspersModified categories
32864view13:52, 16 September 2009SusanModified description
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32860view11:52, 16 September 2009SusanAdding genes
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32858view08:17, 16 September 2009SusanAdding genes and references
32853view12:17, 15 September 2009SusanAdding PI3 kinase
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External references

DataNodes

View all...
NameTypeDatabase referenceComment
4E-BP1GeneProduct1978 (Entrez Gene)
ACC1GeneProduct31 (Entrez Gene)
ACC2GeneProduct32 (Entrez Gene)
ADIPOR1GeneProductENSG00000159346 (Ensembl)
ADIPOR2GeneProductENSG00000006831 (Ensembl)
ADRA1AGeneProductENSG00000120907 (Ensembl)
ADRA1BGeneProductENSG00000170214 (Ensembl)
AMPMetaboliteHMDB0003540 (HMDB)
AMPKa1GeneProduct5562 (Entrez Gene)
AMPKa2GeneProduct5563 (Entrez Gene)
AMPKb1GeneProduct5564 (Entrez Gene)
AMPKb2GeneProduct5565 (Entrez Gene)
AMPKy1GeneProduct5571 (Entrez Gene)
AMPKy2GeneProduct51422 (Entrez Gene)
AMPKy3GeneProduct53632 (Entrez Gene)
ATPMetaboliteHMDB0001532 (HMDB)
AdiponectinGeneProductENSG00000181092 (Ensembl)
Akt1GeneProductENSG00000142208 (Ensembl)
Akt2GeneProductENSG00000105221 (Ensembl)
CAMKK1GeneProductENSG00000004660 (Ensembl)
CAMKK2GeneProductENSG00000110931 (Ensembl)
CCNB1GeneProductENSG00000134057 (Ensembl)
CPT1A (liver)GeneProduct1374 (Entrez Gene)
CPT1B (muscle)GeneProduct1375 (Entrez Gene)
CPT1C (brain)GeneProduct126129 (Entrez Gene)
CalciumMetaboliteHMDB0000464 (HMDB)
Cyclin A1GeneProductENSG00000133101 (Ensembl)
Cyclin A2GeneProductENSG00000145386 (Ensembl)
FA SynthaseGeneProductENSG00000169710 (Ensembl)
Fatty acid oxidationPathwayWP143 (WikiPathways)
GEFGeneProductENSG00000125520 (Ensembl)
GLUT4GeneProduct6517 (Entrez Gene)
GYS1 (muscle)GeneProductENSG00000104812 (Ensembl)
GYS2 (liver)GeneProductENSG00000111713 (Ensembl)
GluconeogenesisPathwayWP534 (WikiPathways)
GlucoseMetaboliteHMDB0000122 (HMDB)
GlycolysisPathwayWP534 (WikiPathways)
HMG CoA reductaseGeneProductENSG00000113161 (Ensembl)
HNF4AGeneProductENSG00000101076 (Ensembl)
HSLGeneProductENSG00000079435 (Ensembl)
HuRGeneProductENSG00000066044 (Ensembl)
INSRGeneProductENSG00000171105 (Ensembl)
InsulinGeneProductENSG00000129965 (Ensembl)
LEPRGeneProductENSG00000116678 (Ensembl)
LKB1GeneProductENSG00000118046 (Ensembl)
LeptinGeneProductENSG00000174697 (Ensembl)
MEF2BGeneProductENSG00000064489 (Ensembl)
MO25GeneProduct51719 (Entrez Gene)
Malonyl-CoAMetaboliteHMDB0001175 (HMDB)
MetforminMetabolite657-24-9 (CAS)
P53GeneProductENSG00000141510 (Ensembl)
PFK2GeneProduct5209 (Entrez Gene)
PGC-1GeneProductENSG00000155846 (Ensembl)
PI3K (III)GeneProductENSG00000078142 (Ensembl)
PLCB1GeneProductENSG00000182621 (Ensembl)
PRKACBGeneProduct5567 (Entrez Gene)
PRKACGGeneProduct5568 (Entrez Gene)
RaptorGeneProduct57521 (Entrez Gene)
SREBP1GeneProductENSG00000072310 (Ensembl)
STRADAGeneProductENSG00000266173 (Ensembl)
STRADBGeneProductENSG00000082146 (Ensembl)
TSC1GeneProductENSG00000165699 (Ensembl)
TSC2GeneProductENSG00000103197 (Ensembl)
Torc2GeneProduct200186 (Entrez Gene)
cAMPMetaboliteHMDB0000058 (HMDB)
eEF2GeneProduct1938 (Entrez Gene)
eEF2KGeneProductENSG00000103319 (Ensembl)
mTORGeneProduct2475 (Entrez Gene)
p110-aGeneProductENSG00000121879 (Ensembl)
p110-b GeneProductENSG00000051382 (Ensembl)
p110-dGeneProductENSG00000171608 (Ensembl)
p110-yGeneProductENSG00000105851 (Ensembl)
p21GeneProduct1026 (Entrez Gene)
p55-yGeneProductENSG00000117461 (Ensembl)
p70S6KaGeneProductENSG00000108443 (Ensembl)
p70S6KbGeneProductENSG00000175634 (Ensembl)
p85-aGeneProductENSG00000145675 (Ensembl)
p85-bGeneProductENSG00000105647 (Ensembl)

Annotated Interactions

No annotated interactions

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