PRKAA1
Description
The PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) is a protein-coding gene located on chromosome 5.
5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the PRKAA1 gene. The protein encoded by this gene belongs to the serine/threonine protein kinase family. It is the catalytic subunit of the 5'-prime-AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor conserved in all eukaryotic cells. The kinase activity of AMPK is activated by the stimuli that increase the cellular AMP/ATP ratio. AMPK regulates the activities of a number of key metabolic enzymes through phosphorylation. It protects cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. Alternatively spliced transcript variants encoding distinct isoforms have been observed. A recent study proposes a role in the metastatic cascade and phenotype determination of pancreatic cancer.
== Interactions == Protein kinase, AMP-activated, alpha 1 has been shown to interact with TSC2.
PRKAA1 encodes the catalytic subunit of AMP-activated protein kinase (AMPK), a critical energy sensor that plays a central role in regulating cellular energy metabolism. AMPK responds to low intracellular ATP levels by activating energy-producing pathways and inhibiting energy-consuming processes, including protein, carbohydrate, and lipid biosynthesis, as well as cell growth and proliferation. It exerts its effects via direct phosphorylation of metabolic enzymes and through longer-term effects via phosphorylation of transcription regulators. Specifically, PRKAA1 regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR, and LIPE. It further regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes. PRKAA1 also promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2). In addition, PRKAA1 regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2, and PFKFB3. PRKAA1 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. Importantly, PRKAA1 regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism, including CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2, and PPARGC1A. Furthermore, PRKAA1 acts as a key regulator of glucose homeostasis in the liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, PRKAA1 phosphorylates 'Ser-36' of histone H2B (H2BS36ph), promoting transcription. PRKAA1 also plays a key role in regulating cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24, and ATG1/ULK1. In response to nutrient limitation, PRKAA1 negatively regulates the mTORC1 complex by phosphorylating the RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. It also phosphorylates and inhibits the GATOR2 subunit WDR24 in response to nutrient limitation, suppressing glucose-mediated mTORC1 activation. In response to energetic stress, PRKAA1 phosphorylates FNIP1, inactivating non-canonical mTORC1 signaling, promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes. Under nutrient limitation, PRKAA1 promotes autophagy by phosphorylating and activating ATG1/ULK1 and also activates WDR45/WIPI4 in this process. PRKAA1 phosphorylates CASP6, preventing its autoprocessing and subsequent activation. In response to nutrient limitation, PRKAA1 phosphorylates transcription factor FOXO3, promoting FOXO3 mitochondrial import. PRKAA1 also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton, possibly by indirectly activating myosin. PRKAA1 further acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to its destabilization. PRKAA1 may regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to its stabilization. PRKAA1 possesses tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, it leads to phosphorylation of MAPT/TAU; however, the relevance of this data remains unclear in vivo. PRKAA1 also phosphorylates CFTR, EEF2K, KLC1, NOS3, and SLC12A1. PRKAA1 regulates hepatic lipogenesis. Activated via SIRT3, it represses sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. Upon stress, PRKAA1 regulates mitochondrial fragmentation through phosphorylation of MTFR1L. AMPK is a heterotrimer composed of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2), and a gamma non-catalytic subunit (PRKAG1, PRKAG2, or PRKAG3). PRKAA1 interacts with FNIP1 and FNIP2.
PRKAA1 is also known as AMPK, AMPK alpha 1, AMPKa1.
