AMPK (PRKAA1) a key regulator of various cellular processes (G5562)

NCBI ID: G5562

PRKAA1

AMPK (PRKAA1) a key regulator of various cellular processes

In the fed state, AMPK inhibits autophagy by activating mTORC1 [1A]. Conversely, during glucose starvation, AMPK is activated and causes mTORC1 to dissociate from lysosomes, thereby reducing its activity [1B]. AMPK activation plays a crucial role in regulating metabolism, protein transportation, transcription factors, and enzymes. It enhances substrate uptake and utilization, promotes mitochondrial biogenesis, and exerts a cardioprotective function. AMPK is also involved in mediating multiple physiological signal pathways. Exercise and exercise-mimetics, such as AICAR, Metformin, and Resveratrol, activate AMPK and positively regulate pathways related to endurance capacity, fat metabolism, and mitochondrial biogenesis. Furthermore, AMPK activation has been linked to vasodilation, angiogenesis, and increased BDNF expression. In conditions of starvation, AMPK activation promotes survival through the inhibition of protein translation, increased UPS activity, and modulation of proteasome and proteostasis genes. AMPK activation is influenced by the AMP/ATP ratio, upstream kinase activity (e.g., LKB1, CaMKKbeta), and upstream phosphatase activity. Once activated, AMPK stimulates catabolic pathways to increase ATP levels and suppresses anabolic pathways. AMPK is considered a central regulator of energy metabolism.

AMPK inhibits mTORC1 in response to glucose starvation through different mechanisms, including the phosphorylation and activation of the mTOR negative regulator tuberous sclerosis complex 2 (TSC2) and the phosphorylation and inhibition of the mTORC1 component regulatory-associated protein of mTOR (Raptor).

Glucose restriction leads to the induction of GADD34 by ATF4, which binds and dephosphorylates TSC2, resulting in mTORC1 inhibition.

TBC1D7, an additional component of the TSC complex, plays a role in the activation of mTORC1 when depleted.

Cells can adapt to oligomycin treatment by undergoing persistent oscillations, stable adaptation at a lower level of ATP, or stable adaptation at a high level of ATP.

The addition of oligomycin blocks ATP production by oxidative phosphorylation, leading to a decrease in ATP levels and an increase in AMPK activity.

Positive feedback regulation increases the rate of flux through glycolysis, subsequently increasing ATP production and reducing AMPK activity.

Negative feedback regulation of glycolysis is triggered by high ATP levels and citrate buildup in the TCA cycle, leading to a reduction in glycolytic flux.

Insulin-treated cells, in the presence of high glucose and glutamine, maintain a high level of glycolytic flux and ATP production, even in the absence of oxidative phosphorylation.

Metformin inhibits mTOR signaling and leads to changes in gene expression in primary hepatocytes.

Suberoylanilide hydroxamic acid treatment affects multiple biological functions and pathways, including the inhibition of AMPK signaling.

eGSM (an experimental compound) can induce autophagy by either activating AMPK or suppressing mTOR activity.

eGSM activates AMPK but not mTOR activity in A549 cells, while it suppresses mTOR but not AMPK activity in SNU2292 cells.

The metabolization of eGSM in A549 cells generates a metabolite that activates AMPK, contributing to the induction of autophagy.

Protein Name: Protein Kinase AMP-activated Catalytic Subunit Alpha 1

Functions: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357). 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 (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). 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 (By similarity). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). 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 (By similarity). 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 (PubMed:11554766, PubMed:11518699, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). 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 (PubMed:14651849, PubMed:18439900, PubMed:20160076, PubMed:21205641). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:20074060, PubMed:12519745)

The "PRKAA1 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about PRKAA1 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

More Common Targets