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- Table of Contents
16 Citations 16 Q&As
14 Citations 4 Q&As
14 Citations 3 Q&As
14 Citations 4 Q&As
21 Citations 4 Q&As
15 Citations 15 Q&As
17 Citations 16 Q&As
4 Citations 16 Q&As
2 Citations 16 Q&As
2 Citations 16 Q&As
1 Citations 5 Q&As
Facts about RAC-alpha serine/threonine-protein kinase.
AKT accounts for the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 sugar transporter to the cell surface. Phosphorylation of PTPN1 in'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling.
Human | |
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Gene Name: | AKT1 |
Uniprot: | P31749 |
Entrez: | 207 |
Belongs to: |
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protein kinase superfamily |
AKT serine/threonine kinase 1; AKT; Akt1; AKT1m; CWS6; EC 2.7.11; EC 2.7.11.1; PKB alpha; PKB; PKBMGC99656; PRKBA; Protein Kinase B Alpha; Protein kinase B; Proto-oncogene c-Akt; rac protein kinase alpha; RAC; RAC-alpha serine/threonine-protein kinase; RAC-alpha; RAC-PK-alpha; RACPKB-ALPHA; Serine-Threonine Protein Kinase ; v-akt murine thymoma viral oncogene homolog 1; V-Akt Murine Thymoma Viral Oncogene-Like Protein 1
Mass (kDA):
55.686 kDA
Human | |
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Location: | 14q32.33 |
Sequence: | 14; NC_000014.9 (104769349..104795748, complement) |
Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.
Cytoplasm. Nucleus. Cell membrane. Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A. Phosphorylation on Tyr-176 by TNK2 results in its localization to the cell membrane where it is targeted for further phosphorylations on Thr-308 and Ser-473 leading to its activation and the activated form translocates to the nucleus. Colocalizes with WDFY2 in intracellular vesicles (PubMed:16792529).
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The function of Akt signaling in muscle is critical for maintaining glucose homeostasis. Akt regulates insulin sensitivity and glucose uptake in muscle, and deficiency in the Akt protein reduces these functions. The resulting muscle mass and glucose utilization are significantly reduced. These findings suggest that Akt plays an important role in the regulation of glucose homeostasis in muscle.
Besides insulin, the PI3K-Akt pathway plays an important role in brain metabolism, synapse formation, and cell growth and survival. The PI3K-Akt pathway is a common denominator in Type 2 diabetes (T2D). Insulin regulates glucose homeostasis in peripheral tissues and is involved in neuronal health. Furthermore, insulin regulates fatty acid and protein metabolism. The typical Western diet is associated with insulin resistance, whereas the PI3K-Akt pathway plays a critical role in T2D pathogenesis.
Insulin can stimulate glucose uptake in M-AktDKO mice, but only if Akt is functional. In mice lacking Akt, insulin-stimulated glucose uptake is inhibited by acute small-molecule inhibition. Lack of Akt may result in compensatory mechanisms for insulin-induced glucose uptake in skeletal muscle. A developmental compensatory pathway may be present in the absence of Akt.
In mice lacking mTORC2, Akt S473 phosphorylation in the BAT decreases when exposed to cold. Conversely, overexpression of constitutively active Akt2 mutant restores glucose uptake and glycolysis in AdRiKO mice. However, in vivo, this mechanism may be different. However, it seems that Akt signaling regulates glucose homeostasis and is important in regulating body temperature.
Further, these findings suggest that novel regulators of NST may be useful for drug discovery. They could provide new drug targets for the treatment of diabetes and obesity. It is possible to manipulate the activity of Akt to control insulin levels. In fact, drug developers may eventually find new targets for insulin and glucagon-releasing hormone. They may even be able to block NST altogether. With more information, this may ultimately lead to improved diabetes care.
In addition to regulating insulin levels, ABM can also increase the levels of PI3K and GLUT4 in diabetic rats. These results suggest that ABM may be a potential health food or diabetes remedy. And although a number of other studies have been done with this new nutrient, the study reveals that Akt signaling is essential for the maintenance of glucose homeostasis in the pancreas.
Akt signaling controls signal transduction in many cell types, including the immune system. It inhibits glycogen synthase kinase 3b (GSK3b) and increases b-catenin activity. Akt kinase activity requires phosphorylation of a serine or threonine residue in the hydrophobic motif. These receptors act on a variety of downstream substrates, including cytokines, which are important for cell survival and growth.
The PI3K/AKT pathway has been implicated in several diseases, including Alzheimer's disease and type 2 diabetes. Researchers have found that manganese is associated with the development of both neurodegenerative and psychiatric disorders. Other important pathways regulated by PI3K/AKT include diabetes mellitus, erythropoiesis, vesicle trafficking, and insulin/IGF-1 signaling.
Akt is a critical regulator of cellular phosphorylation. Phosphorylation of p47Phox by Akt mediates respiratory burst activity in human neutrophils. Activation of Akt impairs Chk1 by phosphorylation, ubiquitination, and reduced nuclear localization. Furthermore, Akt-deregulated tumor cells exhibit increased genomic instability, making them a prime target for anticancer drugs.
Akt-activation is associated with development of a therapeutic resistance to PI3K/AKT inhibitors. However, strategies involving inhibitors of Akt/PI3K could provide new insights for cancer drug development. One effective therapeutic strategy includes combining inhibitors of PI3K/Akt with other anti-cancer agents, such as chemotherapy and radiation. However, this approach may not be effective in all cancer types.
Akt-phosphorylation of P27kip1 is one of the most important steps in angiogenesis. Phosphorylated AKT inhibits the activity of eIF4EBP, a transcription initiation factor, and targets eIF4E for degradation. Similarly, non-phosphorylated PHASI inhibits the synthesis of protein. Hence, Akt and mTOR are critical for the angiogenesis process.
In addition to regulating the signaling pathways, Akt also plays an important role in neurodegeneration. Inhibition of RAS inhibits neuron survival by triggering PI3K activity. Moreover, Akt signals neurotrophins, which are crucial for learning and memory. In addition to neurotrophins, BDNF is also important for neuroplasticity. In fact, BDNF is an essential cytokine for the brain.
Activation of Akt-1 mediates Notch2's pro-survival effects, by suppressing PTEN and inducing IGF-1R. In a breast epithelial cell model, Notch-dependent Akt induction of Notch is maintained through an autocrine loop. This maintains the transformation state. If the Notch-mediated pathway is not working properly, the phenotype of the cell may recur.
Akt regulates many processes in the cell including the regulation of metabolism and ROS. Activated Akt regulates the production and elimination of ROS. AKT phosphorylates FOXO at three conserved residues, inhibiting its nucleus translocation and promoting its ubiquitination. Activated AKT promotes the oxygen consumption of cells, promoting cell division, and rendering cancer cells closer to the death threshold.
Activated AKT promotes de novo lipid synthesis by activating the SREBP family of transcription factors. The SREBP family is responsible for the expression of nearly all fatty acid and sterol synthesis enzymes. This group of transcription factors regulates the expression of PRPP synthase 2 (PRPS2), a protein that catalyzes the ribose-5-phosphate to nucleotide synthesis. SREBP is implicated in MYC-mediated tumorigenesis.
AKT controls the key steps of glycolysis, including the phosphorylation of glycolytic enzymes. It also promotes the activity of hexokinase 2, which phosphorylates glucose into glucose-6-phosphate, which cannot be transported out of the cell. By promoting the activity of HK2, AKT also promotes cell survival by maintaining the integrity of mitochondria. In turn, Akt promotes lipid metabolism and contributes to the synthesis of ATP.
Activation of AKT inhibits the production of antioxidants and reduces cell death. AKT is different from AMPK, and PTEN controls its activity under glucose deprivation. Overexpression of PTEN inhibits AKT activity under glucose deprivation, making lung cancer cells susceptible to glucose withdrawal. However, overexpression of PTEN reverses AKT activation. Activated AKT increases oxygen consumption and decreases FOXO activity.
Proliferating cells need to double their macromolecule content after every cell division. In order to sustain this level, proliferating cells must engage in anabolic processes that drive macromolecule production. This is achieved through the activity of AKT and PI3K. This means that cancer cells may respond poorly to drugs that inhibit PI3K-Akt signaling. There are many possibilities for preventing cancer through the inhibition of Akt.
Moreover, AKT activates PDK1 in hypoxia, which enhances glutathione synthesis. This enzyme has been shown to inhibit xCT function downstream of growth factor signaling. Moreover, AKT phosphorylates xCT and inhibits its activity, preserving NADPH for lipid synthesis. This activity promotes anaplerotic metabolism by maintaining the TCA cycle flux.
AKT stimulates a host of cellular functions, including the production and degradation of NADPH. In addition, Akt signaling regulates the activity of a component of NADPH oxidase, p47phox. This enzyme has dual roles in cancer development and progression. It is a crucial target in cancer therapies. In addition to regulating the levels of NADPH in cancer cells, AKT also inhibits the expression of a variety of other genes.
Metabolic stress is another significant cause of redox imbalance in cancer cells. Metabolic stress disrupts cellular metabolism and redox homeostasis, making cancer cells more vulnerable to apoptosis. However, metabolic stress also impairs the cross-talk between AMPK and AKT and affects the progression and treatment of cancer. This is a complex relationship and requires further research.
PMID: 1851997 by Jones P.F., et al. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily.
PMID: 11508278 by Matsubara A., et al. Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes.
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