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.
|ITGB8||ITGB8 Antibody||ITGB8 Protein||ITGB8 cDNA||ITGB8 ELISA Kit|
|JAK1||JAK1 Antibody||JAK1 Protein||JAK1 cDNA||JAK1 ELISA Kit|
|JAK2||JAK2 Antibody||JAK2 Protein||JAK2 cDNA||JAK2 ELISA Kit|
|JAK3||JAK3 Antibody||JAK3 Protein||JAK3 cDNA||JAK3 ELISA Kit|
|KDR||KDR Antibody||KDR Protein||KDR cDNA||KDR ELISA Kit|
|KIT||KIT Antibody||KIT Protein||KIT cDNA||KIT ELISA Kit|
|KITLG||KITLG Antibody||KITLG Protein||KITLG cDNA||KITLG ELISA Kit|
|KRAS||KRAS Antibody||KRAS Protein||KRAS cDNA||KRAS ELISA Kit|
|LAMA1||LAMA1 Antibody||LAMA1 Protein||LAMA1 cDNA||LAMA1 ELISA Kit|
|LAMA2||LAMA2 Antibody||LAMA2 Protein||LAMA2 cDNA||LAMA2 ELISA Kit|
|LAMA3||LAMA3 Antibody||LAMA3 Protein||LAMA3 cDNA||LAMA3 ELISA Kit|
|LAMA4||LAMA4 Antibody||LAMA4 Protein||LAMA4 cDNA||LAMA4 ELISA Kit|
|LAMA5||LAMA5 Antibody||LAMA5 Protein||LAMA5 cDNA||LAMA5 ELISA Kit|
|LAMB1||LAMB1 Antibody||LAMB1 Protein||LAMB1 cDNA||LAMB1 ELISA Kit|
|LAMB2||LAMB2 Antibody||LAMB2 Protein||LAMB2 cDNA||LAMB2 ELISA Kit|
|LAMB3||LAMB3 Antibody||LAMB3 Protein||LAMB3 cDNA||LAMB3 ELISA Kit|
|LAMB4||LAMB4 Antibody||LAMB4 Protein||LAMB4 cDNA||LAMB4 ELISA Kit|
|LAMC1||LAMC1 Antibody||LAMC1 Protein||LAMC1 cDNA||LAMC1 ELISA Kit|
|LAMC2||LAMC2 Antibody||LAMC2 Protein||LAMC2 cDNA||LAMC2 ELISA Kit|
|LAMC3||LAMC3 Antibody||LAMC3 Protein||LAMC3 cDNA||LAMC3 ELISA Kit|