PRKAA2 gene

The PRKAA2 gene (PRKAA2 stands for: Protein Kinase AMP-Activated Catalytic Subunit Alpha 2) is a protein-coding gene located on chromosome 1p32.2, an important paralog of this gene is PRKAA1. The protein encoded by this gene is a catalytic subunit of AMP-activated protein kinase (AMPK/ Towler MC et al. 2007; Hardie DG 2007). AMPK is a heterotrimer consisting of a catalytic alpha subunit and the non-catalytic beta and gamma subunits. AMPK acts as a sensor for the energy status of cells and ensures survival in times of cellular metabolic stress.

AMPK is an important energy-sensitive enzyme that monitors the energy status of the cell. In response to cellular metabolic stress, AMPK is activated and phosphorylated and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy-beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in the regulation of de novo biosynthesis of fatty acids and cholesterol. Animal murine studies suggest that this catalytic subunit controls whole body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia.

In response to a reduction in intracellular ATP levels, AMPK activates energy-generating pathways and inhibits energy-consuming processes: it inhibits protein, carbohydrate and lipid biosynthesis as well as cell growth and proliferation ( Towler MC et al. 2007; Hardie DG (2007). The enzyme AMPK acts through direct phosphorylation of metabolic enzymes and through longer-term effects via phosphorylation of transcriptional regulators. It regulates lipid synthesis by phosphorylation and inactivation of lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE.

It also regulates fatty acid and cholesterol synthesis by phosphorylating the enzymes acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) (Aguan K et al. (1994). AMK promotes lipolysis of lipid droplets by mediating the phosphorylation of isoform 1 of CHKA (CHKalpha2). The enzyme regulates the insulin signalling pathway and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 and is involved in the internalization of insulin receptor/INSR (Boutchueng-Djidjou M et al. 2015).

AMPK stimulates glucose uptake in muscle by increasing translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160 . The enzyme regulates transcription and chromatin structure by phosphorylating transcriptional regulators involved in energy metabolism, such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (McGee SL et al. 2008). Acts as a key regulator of glucose homeostasis in the liver by phosphorylating CRTC2/TORC2, leading to sequestration of CRTC2/TORC2 in the cytoplasm. Responds to stress by phosphorylating Ser-36" of histone H2B (H2BS36ph), which promotes transcription. Acts as an important regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1. In response to nutrient limitation, it negatively regulates the mTORC1 complex by phosphorylating the RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. Also phosphorylates and inhibits the GATOR2 subunit WDR24 in response to nutrient deprivation, leading to suppression of glucose-mediated mTORC1 activation.

Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably through indirect activation of myosin. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylation of PIK3C3 and activate the pro-autophagy complex by phosphorylation of BECN1

Diseases associated with PRKAA2 include Peutz-Jeghers syndrome. The metabolic pathways involved include selective autophagy and gene expression (transcription).

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