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.
|NGFR||NGFR Antibody||NGFR Protein||NGFR cDNA||NGFR ELISA Kit|
|NOS3||NOS3 Antibody||NOS3 Protein||NOS3 cDNA||NOS3 ELISA Kit|
|NR4A1||NR4A1 Antibody||NR4A1 Protein||NR4A1 cDNA||NR4A1 ELISA Kit|
|NRAS||NRAS Antibody||NRAS Protein||NRAS cDNA||NRAS ELISA Kit|
|NTF3||NTF3 Antibody||NTF3 Protein||NTF3 cDNA||NTF3 ELISA Kit|
|NTF4||NTF4 Antibody||NTF4 Protein||NTF4 cDNA||NTF4 ELISA Kit|
|NTRK1||NTRK1 Antibody||NTRK1 Protein||NTRK1 cDNA||NTRK1 ELISA Kit|
|NTRK2||NTRK2 Antibody||NTRK2 Protein||NTRK2 cDNA||NTRK2 ELISA Kit|
|OSM||OSM Antibody||OSM Protein||OSM cDNA||OSM ELISA Kit|
|OSMR||OSMR Antibody||OSMR Protein||OSMR cDNA||OSMR ELISA Kit|
|PCK1||PCK1 Antibody||PCK1 Protein||PCK1 cDNA||PCK1 ELISA Kit|
|PCK2||PCK2 Antibody||PCK2 Protein||PCK2 cDNA||PCK2 ELISA Kit|
|PDGFA||PDGFA Antibody||PDGFA Protein||PDGFA cDNA||PDGFA ELISA Kit|
|PDGFB||PDGFB Antibody||PDGFB Protein||PDGFB cDNA||PDGFB ELISA Kit|
|PDGFC||PDGFC Antibody||PDGFC Protein||PDGFC cDNA||PDGFC ELISA Kit|
|PDGFD||PDGFD Antibody||PDGFD Protein||PDGFD cDNA||PDGFD ELISA Kit|
|PDGFRA||PDGFRA Antibody||PDGFRA Protein||PDGFRA cDNA||PDGFRA ELISA Kit|
|PDGFRB||PDGFRB Antibody||PDGFRB Protein||PDGFRB cDNA||PDGFRB ELISA Kit|
|PDPK1||PDPK1 Antibody||PDPK1 Protein||PDPK1 cDNA||PDPK1 ELISA Kit|
|PGF||PGF Antibody||PGF Protein||PGF cDNA||PGF ELISA Kit|