AMPK: A Potential Drug Target and Biomarker (G5563)

NCBI ID: G5563

PRKAA2

Other Name(s): 5'-AMP-activated protein kinase, catalytic alpha-2 chain | AMP-activated protein kinase alpha-2 subunit variant 2 | AAPK2_HUMAN | Acetyl-CoA carboxylase kinase | protein kinase, AMP-activated, alpha 2

AMPK: A Potential Drug Target and Biomarker

AMPK, also known as adenosine monophosphate-activated protein kinase or PRKAA2, plays a crucial role in various cellular processes and signaling pathways. Metformin, a commonly used drug for diabetes, has been found to induce cell death in melanoma cells through both AMPK-dependent and -independent pathways. AMPK activation is mediated by metabolite sensors such as aldolase, Sestrin, CASTOR1, and SAMTOR, which sense and signal the availability of glucose, arginine, leucine, and SAM/methionine, respectively. Activation of AMPK by PMI-5011/KOE has been observed in muscle cells, and it can occur through different mechanisms, including direct binding to the gamma subunit of AMPK, promoting Thr172-phosphorylation of the alpha subunit, or inhibiting Thr172-dephosphorylation. In failing hearts, AMPK activation has been shown to attenuate cardiac hypertrophy and improve oxidative phosphorylation through regulation of glucose transporters, fatty acid uptake, and inhibition of the mTORC1 pathway. Additionally, increased expression of PRKAA2 has been observed in induced sinoatrial bodies, indicating its potential role in pacemaking and AMPK-mediated signaling. These findings highlight the diverse functions and regulatory mechanisms of AMPK in various biological contexts.
Based on the provided context information, here is a comprehensive summary of the AMPK (also known as PRKAA2) signaling pathway:

AMPK is a key regulator of cellular energy status and plays a role in energy homeostasis. It acts as a sensor of cellular energy and coordinates energy reserves with biosynthetic activity by regulating mTORC1.

AMPK activation occurs on the surface of the lysosome and signals a need for catabolic activity while suppressing mTORC1. This recruitment of AMPK to the lysosomal surface requires the addition of a myristic acid lipid tail.

In female magpies, AMPK is upregulated in the AMPK signaling pathway, suggesting a role in mediating dietary restriction. This pathway is involved in energy metabolism and activates glucose and fatty acid uptake and oxidation while inhibiting gluconeogenesis, glycogen synthesis, and protein synthesis.

AMPK activation in female magpies may help regulate energy dynamics induced by stress resistance. This is supported by the upregulation of G6Pase, an enzyme involved in gluconeogenesis and glycogenolysis.

Male magpies, on the other hand, upregulate genes encoding SIRT1, another enzyme associated with stress resistance and longevity. This indicates that males regulate longevity through SIRT1 and CREB stress resistance genes.

AMPK is also implicated in spermatogenesis, where it regulates tight junction (TJ) dynamics, lactate production, and Sertoli cell proliferation. It co-localizes with mTORC1 on the lysosomal surface and suppresses mTORC1 activity.

In a melanoma context, enhanced production of phosphatidic acid (PA) by overexpression of PLD leads to aberrant mTOR activation in the absence of LKB1/AMPK regulation. This dysregulation results in increased cell proliferation and growth.

In summary, AMPK plays a crucial role in cellular energy homeostasis and is involved in various biological processes such as energy metabolism, stress resistance, longevity, and spermatogenesis. Its dysregulation or aberrant activation can have implications in disease contexts, highlighting the importance of understanding its mechanisms of action.

Protein Name: Protein Kinase AMP-activated Catalytic Subunit Alpha 2

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 (PubMed:7959015). 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). Involved in insulin receptor/INSR internalization (PubMed:25687571). 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: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). 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 acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). 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 (By similarity). Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity)

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•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
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•   expression level;
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