The phosphatidylinositol 3' –kinase (PI3K)-Akt signaling pathway is an intracellular signaling pathway important in regulating the cell cycle and is activated by many types of cellular stimuli or toxic insults.
It regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival in response to extracellular signals. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates.
As shown in following picture, activation of growth factor receptor protein tyrosine kinases including epidermal growth factor receptor (EGFR) by external growth factors results in auto-phosphorylation on tyrosine residues and subsequent events to activate these intracellular pathways.
PI3K is recruited to the membrane by directly binding to phosphotyrosine consensus residues of growth factor receptors or adaptors through one or both SH2 domains in the adaptor subunit. This leads to allosteric activation of the catalytic subunit. Activation results in production of the second messenger phosphatidylinositol-3, 4, 5-trisphosphate (PIP3).
The lipid product of PI3K, PIP3, recruits a subset of signaling proteins with pleckstrin homology (PH) domains to the membrane, including PDK1 and Akt. PTEN, is a PI-3, 4, 5-P3 phosphatase, which negatively regulates the PI3K/Akt pathway.
Once activated, Akt mediates the activation and inhibition of several targets, resulting in cellular survival, growth and proliferation through various mechanisms. In the mechanism of PI3K-Akt signaling pathway, the key molecules involved in this signaling pathway are receptor tyrosine kinase (RTKs), phosphatidylinositol 3-kinase (PI3K), phosphatidylinositol-4,5-bisphosphate (PIP2), phosphatidylinositol-3,4,5-bisphosphate (PIP3) and AKT/protein kinase B.
Most genetic alterations associated with tumor phenotype are representative of a finite succession of physiologic disturbances, which, collectively, render the cell to become malignant. Alterations of the PI3K-Akt signaling pathway have been reported in numerous human cancers. The PI3K-Akt signaling pathway plays an important role in the characteristic process of cancer. For example, Akt overexpression or activation may lead to an increased response to ambient levels of growth factors. Sustained activation of Akt makes tumor cells insensitive to anti-proliferative signals by inducing nuclear entry of Mdm2, which leads to inhibition of p53 regulated processes and by inducing cytoplasmic localization of p21Cip/Waf1 and p27Kip, which promotes proliferation. Akt activation also suppresses apoptosis of cancer cells by inactivating pro-apoptotic factors Bad and pro-caspase-9, but by activating IKK that provokes the transcription of NF-κB regulated antiapoptotic genes. Besides, the PI3K-Akt pathway also promotes tumor angiogenesis through eNOS activation and contributes to invasiveness by inhibiting anoikis and stimulating MMP secretion.
There are numerous aberrant mutations of the PI3K-Akt pathway in human cancers, including loss of the lipid phosphatases PTEN and INPP4B, as well as mutation and amplification of the genes encoding the PI3K catalytic subunits p110α (PIK3CA) and p110β (PIK3CB), and so on. In recent clinic cancer treatment, several drugs targeting the PI3K-Akt pathway have been developed and are currently in clinical trials in different phases of clinical development, such as PI3K Inhibitors, Isoform-Specific PI3K Inhibitors, Dual PI3K/mTOR Inhibitors. However, these drugs are just observed early signals of clinical activity. A better understanding of this essential crossroad between PI3K-Akt signaling and cancer is conducive to fully exploit the potential benefits of these new drugs.
Under normal conditions, insulin is immediately secreted after a meal. The released insulin binds to and activates IRS-1/2 (insulin receptor substrate-1/2), initiating the PI3K-Akt signaling pathway. Insulin-mediated Akt pathway accelerates glucose utilization, reduces gluconeogenesis of liver and muscle, increases body lipid deposition, thereby reducing free fatty acid (FFA) circulation in adipose tissue, increases pancreatic insulin secretion, and regulates lipid and glucose metabolism balance, reduce brain appetite. However, in the case of chronic energy excessive conditions, such as obesity, lipid accumulation is saturated, resulting in increased lipolysis of adipose tissue, leading to excessive FFAs. Lipid ectopic accumulation of skeletal muscle leads to reduced glucose transport and glycogen synthesis. Excess FAAs also disrupts β-cell function and insulin secretion. In the liver, excess FAAs suppress extrahepatic insulin signal transduction and ectopic accumulation of lipids, leading to an increase in HGP (hepatic glucose production) and DNL (de novo lipogenesis). In the brain, excessive FFAs cause glucose and lipid metabolism disorders. All these eventually impairs the PI3K-Akt signal, inducing insulin resistance. Insulin resistance further exacerbates the PI3K-AKT signal, forming a vicious circle that leads to obesity and Type II diabetes. As the PI3K-Akt pathway is closely related to metabolism, regulation of PI3K-Akt signaling pathway and its downstream molecules is a potential therapeutic target for the treatment of obesity and type 2 diabetes.
|GYS2||GYS2 Antibody||GYS2 Protein||GYS2 cDNA||GYS2 ELISA Kit|
|HGF||HGF Antibody||HGF Protein||HGF cDNA||HGF ELISA Kit|
|HRAS||HRAS Antibody||HRAS Protein||HRAS cDNA||HRAS ELISA Kit|
|HSP90AA1||HSP90AA1 Antibody||HSP90AA1 Protein||HSP90AA1 cDNA||HSP90AA1 ELISA Kit|
|HSP90AB1||HSP90AB1 Antibody||HSP90AB1 Protein||HSP90AB1 cDNA||HSP90AB1 ELISA Kit|
|HSP90B1||HSP90B1 Antibody||HSP90B1 Protein||HSP90B1 cDNA||HSP90B1 ELISA Kit|
|IBSP||IBSP Antibody||IBSP Protein||IBSP cDNA||IBSP ELISA Kit|
|IFNA1||IFNA1 Antibody||IFNA1 Protein||IFNA1 cDNA||IFNA1 ELISA Kit|
|IFNA10||IFNA10 Antibody||IFNA10 Protein||IFNA10 cDNA||IFNA10 ELISA Kit|
|IFNA13||IFNA13 Antibody||IFNA13 Protein||IFNA13 cDNA||IFNA13 ELISA Kit|
|IFNA14||IFNA14 Antibody||IFNA14 Protein||IFNA14 cDNA||IFNA14 ELISA Kit|
|IFNA16||IFNA16 Antibody||IFNA16 Protein||IFNA16 cDNA||IFNA16 ELISA Kit|
|IFNA17||IFNA17 Antibody||IFNA17 Protein||IFNA17 cDNA||IFNA17 ELISA Kit|
|IFNA2||IFNA2 Antibody||IFNA2 Protein||IFNA2 cDNA||IFNA2 ELISA Kit|
|IFNA21||IFNA21 Antibody||IFNA21 Protein||IFNA21 cDNA||IFNA21 ELISA Kit|
|IFNA4||IFNA4 Antibody||IFNA4 Protein||IFNA4 cDNA||IFNA4 ELISA Kit|
|IFNA5||IFNA5 Antibody||IFNA5 Protein||IFNA5 cDNA||IFNA5 ELISA Kit|
|IFNA6||IFNA6 Antibody||IFNA6 Protein||IFNA6 cDNA||IFNA6 ELISA Kit|
|IFNA7||IFNA7 Antibody||IFNA7 Protein||IFNA7 cDNA||IFNA7 ELISA Kit|
|IFNAR1||IFNAR1 Antibody||IFNAR1 Protein||IFNAR1 cDNA||IFNAR1 ELISA Kit|