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.
|PPP2R2B||PPP2R2B Antibody||PPP2R2B Protein||PPP2R2B cDNA||PPP2R2B ELISA Kit|
|PPP2R2C||PPP2R2C Antibody||PPP2R2C Protein||PPP2R2C cDNA||PPP2R2C ELISA Kit|
|PPP2R2D||PPP2R2D Antibody||PPP2R2D Protein||PPP2R2D cDNA||PPP2R2D ELISA Kit|
|PPP2R3A||PPP2R3A Antibody||PPP2R3A Protein||PPP2R3A cDNA||PPP2R3A ELISA Kit|
|PPP2R3B||PPP2R3B Antibody||PPP2R3B Protein||PPP2R3B cDNA||PPP2R3B ELISA Kit|
|PPP2R3C||PPP2R3C Antibody||PPP2R3C Protein||PPP2R3C cDNA||PPP2R3C ELISA Kit|
|PPP2R5A||PPP2R5A Antibody||PPP2R5A Protein||PPP2R5A cDNA||PPP2R5A ELISA Kit|
|PPP2R5B||PPP2R5B Antibody||PPP2R5B Protein||PPP2R5B cDNA||PPP2R5B ELISA Kit|
|PPP2R5C||PPP2R5C Antibody||PPP2R5C Protein||PPP2R5C cDNA||PPP2R5C ELISA Kit|
|PPP2R5D||PPP2R5D Antibody||PPP2R5D Protein||PPP2R5D cDNA||PPP2R5D ELISA Kit|
|PPP2R5E||PPP2R5E Antibody||PPP2R5E Protein||PPP2R5E cDNA||PPP2R5E ELISA Kit|
|PRKAA1||PRKAA1 Antibody||PRKAA1 Protein||PRKAA1 cDNA||PRKAA1 ELISA Kit|
|PRKAA2||PRKAA2 Antibody||PRKAA2 Protein||PRKAA2 cDNA||PRKAA2 ELISA Kit|
|PRKCA||PRKCA Antibody||PRKCA Protein||PRKCA cDNA||PRKCA ELISA Kit|
|PRL||PRL Antibody||PRL Protein||PRL cDNA||PRL ELISA Kit|
|PRLR||PRLR Antibody||PRLR Protein||PRLR cDNA||PRLR ELISA Kit|
|PTEN||PTEN Antibody||PTEN Protein||PTEN cDNA||PTEN ELISA Kit|
|PTK2||PTK2 Antibody||PTK2 Protein||PTK2 cDNA||PTK2 ELISA Kit|
|RAC1||RAC1 Antibody||RAC1 Protein||RAC1 cDNA||RAC1 ELISA Kit|
|RAF1||RAF1 Antibody||RAF1 Protein||RAF1 cDNA||RAF1 ELISA Kit|