AMPK Signaling (Bos taurus)

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Metformin13, 166, 105, 11151, 37, 81421294GlycogensynthesisHepatic Fatty Acidand VLDL SynthesisBRAINSterol/IsoprenoidSynthesisGLUT4 translocationAMP kinase/GLUT4Gene ExpressionExpression ofMitochondrialGenes in MusclePI3 kinaseLow glucose,Hypoxia, Ischemia,Heat shockTP53HMGCRADRA1BINSELAVL1CCNA2CCNA1GlycolysisGlucoseCDKN1ACCNB1ADRA1AAKT2PIK3R3CAMKK2ADIPOR2RPS6KB1EIF4EBP1PRKAG3GYS1TSC2PRKAA1AKT1ACC1OBSREBF1cAMPIR-APIK3C3PRKAG2MTORPRKAG1PIK3R1STRADAPRKAB2TSC1PIK3CBPIK3CASTRADBADIPOR1PPARGC1BHSLPRKAB1PLCB1MEF2BEEF2KCPT1BSLC2A4FASNRPS6KB2CPT1ATorc2ATPCalciumHNF4AOB-RPFKFB3PIK3CGAMPSLC2A4RGGYS2CAMKK1STK11Malonyl-CoAEEF2CAB39CPT1CPRKACBPIK3CDPRKAA2RPTORPIK3R2ADIPOQPRKACGACACBGLUT4 vesicleLipolysisProtein synthesisGluconeogenesisFatty Acid Oxidation


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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP1403(79471) with a 95.0% conversion rate.

Quality Tags

Ontology Terms

 

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
  2. 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
  3. 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
  4. Shaw RJ; ''LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.''; Acta Physiol (Oxf), 2009 PubMed
  5. Fu A, Screaton RA; ''Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family.''; Cell Cycle, 2008 PubMed
  6. 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
  7. 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
  8. Inoki K, Zhu T, Guan KL; ''TSC2 mediates cellular energy response to control cell growth and survival.''; Cell, 2003 PubMed
  9. 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
  10. 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
  11. Cheng A, Saltiel AR; ''More TORC for the gluconeogenic engine.''; Bioessays, 2006 PubMed
  12. 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
  13. 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
  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
  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
  16. 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

History

CompareRevisionActionTimeUserComment
90026view19:34, 8 October 2016AlexanderPicoModified description
89799view11:28, 6 October 2016Mkutmonfixed special characters in description
89542view11:25, 16 September 2016Mkutmonremove redundant ontology tag in GPML
80719view15:23, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACACBGeneProductENSBTAG00000022058 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:32
ACC1GeneProduct
ADIPOQGeneProductENSBTAG00000019813 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000181092
ADIPOR1GeneProductENSBTAG00000009727 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000159346
ADIPOR2GeneProductENSBTAG00000009050 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000006831
ADRA1AGeneProductENSBTAG00000031632 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000120907
ADRA1BGeneProductENSBTAG00000040253 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000170214
AKT1GeneProductENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000142208
AKT2GeneProductENSBTAG00000001400 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105221
AMPMetaboliteHMDB03540 (HMDB)
ATPMetaboliteHMDB01532 (HMDB)
CAB39GeneProductENSBTAG00000040055 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51719
CAMKK1GeneProductENSBTAG00000007166 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000004660
CAMKK2GeneProductENSBTAG00000010815 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000110931
CCNA1GeneProductENSBTAG00000007284 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000133101
CCNA2GeneProductENSBTAG00000004943 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000145386
CCNB1GeneProductENSBTAG00000014239 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000134057
CDKN1AGeneProductENSBTAG00000008353 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1026
CPT1AGeneProductENSBTAG00000021999 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1374
CPT1BGeneProductENSBTAG00000016048 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1375
CPT1CGeneProductENSBTAG00000012205 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:126129
CalciumMetaboliteHMDB00464 (HMDB)
EEF2GeneProductENSBTAG00000004258 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1938
EEF2KGeneProductENSBTAG00000017662 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000103319
EIF4EBP1GeneProductENSBTAG00000027654 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1978
ELAVL1GeneProductENSBTAG00000000613 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000066044
FASNGeneProductENSBTAG00000015980 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000169710
Fatty Acid OxidationPathwayWP143 (WikiPathways)
GYS1GeneProductENSBTAG00000039958 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000104812
GYS2GeneProductENSBTAG00000013333 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000111713
GluconeogenesisPathwayWP534 (WikiPathways)
GlucoseMetaboliteHMDB00122 (HMDB)
GlycolysisPathwayWP534 (WikiPathways)
HMGCRGeneProductENSBTAG00000007840 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000113161
HNF4AGeneProductENSBTAG00000012116 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000101076
HSLGeneProductENSBTAG00000038321 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000079435
INSGeneProductENSBTAG00000013003 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000129965
IR-AGeneProductENSBTAG00000012687 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171105
MEF2BGeneProduct
MTORGeneProductENSBTAG00000015325 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2475
Malonyl-CoAMetaboliteHMDB01175 (HMDB)
MetforminMetabolite657-24-9 (CAS)
OB-RGeneProductENSBTAG00000005910 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000116678
OBGeneProductENSBTAG00000014911 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000174697
PFKFB3GeneProductENSBTAG00000008401 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5209
PIK3C3GeneProductENSBTAG00000026290 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000078142
PIK3CAGeneProductENSBTAG00000009232 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000121879
PIK3CBGeneProductENSBTAG00000006909 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000051382
PIK3CDGeneProductENSBTAG00000018984 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000171608
PIK3CGGeneProductENSBTAG00000020848 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105851
PIK3R1GeneProductENSBTAG00000010989 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000145675
PIK3R2GeneProductENSBTAG00000002350 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000105647
PIK3R3GeneProductENSBTAG00000002979 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000117461
PLCB1GeneProductENSBTAG00000008338 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000182621
PPARGC1BGeneProductENSBTAG00000012943 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000155846
PRKAA1GeneProductENSBTAG00000000013 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5562
PRKAA2GeneProductENSBTAG00000018747 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5563
PRKAB1GeneProductENSBTAG00000005940 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5564
PRKAB2GeneProductENSBTAG00000014387 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5565
PRKACBGeneProductENSBTAG00000011953 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5567
PRKACGGeneProduct
PRKAG1GeneProductENSBTAG00000014426 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5571
PRKAG2GeneProductENSBTAG00000002917 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51422
PRKAG3GeneProductENSBTAG00000013492 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:53632
RPS6KB1GeneProductENSBTAG00000016851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000108443
RPS6KB2GeneProductENSBTAG00000009175 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000175634
RPTORGeneProductENSBTAG00000002883 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:57521
SLC2A4GeneProductENSBTAG00000009190 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6517
SLC2A4RGGeneProductENSBTAG00000016664 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000125520
SREBF1GeneProductENSBTAG00000007884 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000072310
STK11GeneProductENSBTAG00000011639 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000118046
STRADAGeneProductENSBTAG00000000056 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000266173
STRADBGeneProductENSBTAG00000019298 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000082146
TP53GeneProductENSBTAG00000001069 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000141510
TSC1GeneProductENSBTAG00000005190 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000165699
TSC2GeneProductENSBTAG00000020617 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000103197
Torc2GeneProductENSBTAG00000047190 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:200186
cAMPMetaboliteHMDB00058 (HMDB)

Annotated Interactions

No annotated interactions
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