About Phosphoinositide 3-kinase:
Phosphoinositide 3-Kinases (PI3Ks) are a family of enzymes which play a pivotal role in a range of cellular functions including cell growth, proliferation, differentiation, motility and intracellular trafficking. Thus, a great deal of their interactions are involved in cancer.
They are intracellular signal transducer enzymes which are able to phosphorylate the 3 position hydroxyl groups of the inositol ring of Phosphatidylinositol (PtdIns). This pathway, alongside oncogene PIK3CA and tumor suppressor PTEN, is implicated in the sensitivity of cancer tumors to insulin and calorie restriction.
PI3-kinase Mechanism
Numerous 3-phosphorylated phosphoinositides are produced by PI3Ks but all share a common mechanism by which group of signalling proteins are recruited to a range of cellular membranes.
Studies show that when PI3K) is combined with AKT (Protein Kinase B) the PI3K/AKT pathway is required for a highly diverse array of cellular activities. The most notable ate the proliferation of different cells and cellular survival rates. A key example was the protection of astrocytes from ceramide-induced apoptosis.
Phosphoinositide 3-kinase Function
PI3Ks have been linked to the regulation of isoforms to control numerous different aspects of immune responses. They are, for instance a key component of the insulin signaling pathway. As such, PI3K signaling is of great interest to the medical and pharmaceutical communities in the treatment and prevention of diabetes.
PI3-kinase Interactions
PI3K activity has been proven to play a significant part in cellular transformation and the development of cancer. TClasses of PI3K can mutate into a range of cancers. Many of these mutations can cause over-activation of the kinase to be more active as is seen in the case of the most malignant primary brain tumour glioblastoma.Learning and memory are also proven to be affected by PI3Ks. They have been implicated in Long-Term Potentiation (LTP)- a strengthening of the synapses based on recent patterns of activity. However, how essential they are in expressing or the inducing LTP is the subject of some debate.
Studies with mouse hippocampal neurons showed some PI3Ks to be complexed with AMPA receptors and compartmentalized at the postsynaptic density of glutamatergic synapses.
This suggests that PI3Ks are required for the expression of LTP but debate continues.
Moreover, PI3K inhibitors have been demonstrated to abolish the expression of LTP in rat hippocampal without affecting its induction. Evidence suggests that dependence of late-phase LTP expression on PI3Ks decreases as time goes by.
The PI3K pathway also recruits a range of other proteins downstream. These include pathways which lead to the phosphorylation of kinases known to facilitate translational activity. This further suggests that PI3Ks are required for the protein-synthesis phase of LTP induction.
All PI3Ks are inhibited by the drugs wortmannin and LY294002. However, clinical trials have proven that certain members of the class II PI3K family show decreased sensitivity. Wortmannin, for example, shows better efficiency than LY294002 on the hotspot mutation positions (GLU542, GLU545, and HIS1047)
Phosphoinositide 3-kinase Structure
The PI3K family is divided into four different classes: Class I, Class II, Class III, and Class IV. These classifications are based on a range of factors including their primary structures, regulation, and the lipid specificity of their substrates in vitro.