PRKAA2 - 5'-AMP-activated protein kinase catalytic subunit alpha-2 - human protein (Function)
 
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PRKAA2 »  5'-AMP-activated protein kinase catalytic subunit alpha-2   [ EC 2.7.11.1 ]  (AMPK subunit alpha-2)
 
Protein also known as:  Hydroxymethylglutaryl-CoA reductase kinase [EC 2.7.11.31] (HMGCR kinase).
Gene name:  PRKAA2
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.  
12
  • CuratedUniProtKB
GO molecular function 
[acetyl-CoA carboxylase] kinase activitydefinition[GO:0050405]  
  • IEAEC 2 GO
[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activitydefinition[GO:0047322]  
  • IEAEC 2 GO
AMP-activated protein kinase activitydefinition[GO:0004679]  
1
  • IDAUniProtKB
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Chromatin bindingdefinition[GO:0003682]  
  • ISSOrtholog Curator
Histone serine kinase activitydefinition[GO:0035174]  
  • ISSOrtholog Curator
Metal ion bindingdefinition[GO:0046872]  
  • IEAUniProtKB KW
Protein bindingdefinition[GO:0005515]  
2
  • IPIUniProtKB
Protein kinase activitydefinition[GO:0004672]  
1
  • TASPINC
Protein serine/threonine kinase activitydefinition[GO:0004674]  
  • ISSOrtholog Curator
GO biological process 
Autophagydefinition[GO:0006914]  
  • IEAUniProtKB KW
Cellular response to glucose starvationdefinition[GO:0042149]  
  • ISSOrtholog Curator
Cellular response to nutrient levelsdefinition[GO:0031669]  
  • ISSOrtholog Curator
Cholesterol biosynthetic processdefinition[GO:0006695]  
  • IEAUniProtKB KW
Fatty acid biosynthetic processdefinition[GO:0006633]  
  • IEAUniProtKB KW
Fatty acid homeostasisdefinition[GO:0055089]  
  • ISSOrtholog Curator
Glucose homeostasisdefinition[GO:0042593]  
  • ISSOrtholog Curator
Lipid biosynthetic processdefinition[GO:0008610]  
  • ISSOrtholog Curator
Negative regulation of apoptotic processdefinition[GO:0043066]  
  • ISSOrtholog Curator
Negative regulation of TOR signalingdefinition[GO:0032007]  
  • ISSOrtholog Curator
Positive regulation of autophagydefinition[GO:0010508]  
  • ISSOrtholog Curator
Positive regulation of glycolytic processdefinition[GO:0045821]  
  • ISSOrtholog Curator
Protein phosphorylationdefinition[GO:0006468]  
1
  • TASPINC
Regulation of circadian rhythmdefinition[GO:0042752]  
  • ISSOrtholog Curator
Regulation of energy homeostasisdefinition[GO:2000505]  
  • ISSOrtholog Curator
Regulation of transcription, DNA-templateddefinition[GO:0006355]  
  • IEAUniProtKB KW
Response to stressdefinition[GO:0006950]  
  • ISSOrtholog Curator
Rhythmic processdefinition[GO:0048511]  
  • IEAUniProtKB KW
Signal transductiondefinition[GO:0007165]  
1
  • TASPINC
Transcription, DNA-templateddefinition[GO:0006351]  
  • IEAUniProtKB KW
Wnt signaling pathwaydefinition[GO:0016055]  
  • IEAUniProtKB KW
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reactions
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
EC 2.7.11.31: ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate.  
  • CuratedUniProtKB
EC 2.7.11.27: ATP + [acetyl-CoA carboxylase] ADP + [acetyl-CoA carboxylase] phosphate.  
  • CuratedUniProtKB
It requires the following cofactor
Magnesium (By similarity).  
  • CuratedUniProtKB
It is regulated in the following manner
Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.  
4
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Adipocytokine signaling pathway  hsa04920+5563  
Hypertrophic cardiomyopathy (HCM)  hsa05410+5563  
Insulin signaling pathway  hsa04910+5563  
mTOR signaling pathway  hsa04150+5563  
Regulation of autophagy  hsa04140+5563  
According to Reactome, this protein belongs to the following pathways:
Membrane Trafficking  REACT_11123  
Metabolism  REACT_111217  
Organelle biogenesis and maintenance  REACT_200751  
Signal Transduction  REACT_111102  
 

Keywords

Biological process 
Autophagy  definition   [KW-0072]
Biological rhythms  definition   [KW-0090]
Cholesterol biosynthesis  definition   [KW-0152]
Cholesterol metabolism  definition   [KW-0153]
Fatty acid biosynthesis  definition   [KW-0275]
Fatty acid metabolism  definition   [KW-0276]
Lipid biosynthesis  definition   [KW-0444]
Lipid metabolism  definition   [KW-0443]
Steroid biosynthesis  definition   [KW-0752]
Steroid metabolism  definition   [KW-0753]
Sterol biosynthesis  definition   [KW-0756]
Sterol metabolism  definition   [KW-1207]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Wnt signaling pathway  definition   [KW-0879]
Molecular function 
Chromatin regulator  definition   [KW-0156]
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: PRKAA2
GenomeRNAi: 5563
PRO: PR:P54646
Chemistry
GuidetoPHARMACOLOGY: 1542