The PI3K-AKT signaling pathway is involved in several key steps of the cell cycle1, thus mediating cell growth and proliferation, survival, and metabolism under normal conditions2. This pathway functions downstream of several receptor tyrosine kinases, where phosphorylation of PI3K by the cytoplasmic tyrosine kinase domain of the receptor activates the enzyme3. In fact, initial interest in studying AKT signaling grew because of its mediation of the insulin signaling pathway downstream of the insulin receptor and the insulin-like growth factor I receptor4. At the interior cell membrane, PI3K then phosphorylates the secondary mediator PIP2 to PIP3; PIP3 recruits AKT to the interior cell membrane. Activation of AKT is a multi-step process, whereby AKT undergoes a conformational change to expose a phosphorylation site at threonine 308, which is then phosphorylated by PDK1. A second site on AKT at serine 473 can also be phosphorylated, although the enzyme responsible for this has yet to be elucidated. These activities can be regulated by the activity of PTEN, a 3’-phosphatase that dephosphorylates PI3K and renders it unable to activate AKT3.
Following its activation, AKT translocates from the membrane to the cytosol and nucleus, where it regulates several components of cell cycle progression. AKT is upstream of the mammalian target of rapamycin (mTOR) complexes mTORC1 and mTORC2. Both mTOR complexes are protein kinases that promote cell growth and inhibit autophagy5. mTORC1 is regulated by the tuberous sclerosis complex 1/2, which can be phosphorylated and inactivated by AKT. Interestingly, mTORC2 may function both upstream and downstream of AKT, propagating a positive feedback loop, as it is thought to be one of the kinases capable of phosphorylating serine 473. AKT is also involved in the inhibition of apoptosis by phosphorylating FOXO transcription factors and glycogen synthase kinase 3 (GSK3), which are then inhibited3.
Defects in PI3K-AKT signaling may arise proximal to the receptor or further downstream. Because AKT as a downstream mediator of signaling is ubiquitous and involved in multiple signaling pathways including IGF and EGFR6, dysregulation of AKT leads to disease states. Many cancers are driven by mutations in this pathway, including: gastric cancer7, ovarian cancer8, breast cancer9, kidney cancer10, bladder cancer11, lung cancer12, and others. AKT can mediate primary tumor development13, resistance to chemotherapy14, and dissemination of metastatic disease15. As a result, several therapeutics targeted at inhibiting AKT activity are currently in clinical trials16.
Other diseases reported to have AKT-dependent pathologies include amyotrophic lateral sclerosis17, non-alcoholic fatty liver disease18,19, chronic obstructive pulmonary disease (COPD)20, Alzheimer’s disease21, and Type 2 diabetes22. Therapeutic interventions targeting AKT in some of these diseases are currently being developed in animal models with the goal of increasing AKT activity to prevent tissue damage. In particular, pharmacologic activation of AKT in a murine model of Alzheimer’s disease appeared to improve cognitive function21. In non-alcoholic fatty liver disease, GCSF treatment reduced hepatocyte apoptosis in association with increased PI3K and AKT activity18, and treatment with the antioxidant scutellarin led to improved disease biomarkers correlated with an increase in PI3K-AKT expression levels19.
The PI3K-AKT pathway mediates a multitude of signaling pathways in throughout the body, and plays a role in the pathology of many diseases. To help scientists better understand this pathway in the context of their research, Bethyl manufacturers many antibodies to components of the PI3K-AKT pathway.
Detection of human PTEN in FFPE breast carcinoma by IHC. Antibody: Rabbit anti-PTEN (A300-701A). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.
Below is the entire list of targets involved in PI3K-AKT signaling pathway research. Can’t find what you are looking for? Bethyl offers a custom antibody service.