PI3K/AKT Signaling In Cancer

Published on December 5, 2011   68 min

Other Talks in the Series: Protein Phosphorylation

I am speaking today about the PI3K signaling pathway in cancer. This is one of the most commonly activated and mutated pathways in cancer, and we believe it plays an important role in the development of cancer and offers us the opportunity to develop drugs that inhibit this pathway, ought to be very useful in treatments. PI3 kinase is an important signaling pathway in normal physiology.
It regulates metabolism, cell growth, cell migration, and cell survival. One of its key functions is regulation of metabolism and glucose homeostasis because it's the most important downstream effector pathway that is activated by the insulin and IGF-1 molecules. The way this works is insulin or IGF-1 bind to a receptor, either the insulin receptor or IGF-1 receptor, and this causes the activation of the receptor. The activated receptor phosphorylates a whole variety of substrates including the IRS molecules. Phosphorylation of these molecules causes their recruitment to an activation of a variety of intracellular signaling molecules. For the purpose of this talk, the most important one of these is PI3 kinase. PI3 kinase is an enzyme that consists of two sub-units, a regulatory sub-unit which in this case is an 85 kilodalton sub-unit, and a catalytic subunit, 110 kilodaltons. This is a big family, but these are the most commonly studied, the class 1 kinases. What this enzyme does is it phosphorylates phosphatidylinositol on the three position which causes the formation of PIP3. PIP3, which becomes phosphorylated in other positions, the four and five position, binds to a whole variety of proteins in the cell that have PH domains. It binds to the phosphorylated phosphatidylinositol, PIP3, 4 or 5, and causes it to dock to the plasma membrane where it becomes activated by phosphorylation. There are many such targets of the phosphorylated phosphatidylinositols but the one that is most well defined and most known to be important in cancer is the Akt kinase. Akt kinase gets activated by phosphorylation after it binds to the membrane. Phosphorylation on a serine at 473 and a threonine at 308, and Akt then becomes activated and phosphorylates a whole variety of substrates that are important in preventing cell death, inducing cell growth, regulating metabolism, and inducing translation. This whole pathway is down-regulated by a variety of negative regulatory mechanisms including the PTEN protein. The PTEN protein is a phosphatase that de-phosphorylates the phosphatidylinositolphosphates on the three position, thus turning off the pathway. In the cell, the PI3 kinase pathway is regulated by