Grant: Operating Grant - PA: Regional Partnership Program - Saskatchewan

The function of the PTEN protein in normal cells is to turn off cellular pathways that cause cell growth and cell survival. So PTEN blocks tumor formation. In many different kinds of human cancers (e.g. breast, prostate and endometrium), the PTEN protein is present at reduced levels, or contains mutations that make it less effective. When the PTEN protein is missing, or even reduced, cells grow in an uncontrolled way and form a tumor. PTEN is also important in controlling cellular responses to insulin and may be a suitable target for treatment of patients with type II diabetes. PTEN activity modifies an important component of the cell membrane. We have previously discovered that the p85 protein can bind to and increase the activity of PTEN, making it more effective at suppressing tumor formation. In this proposal, we will characterize PTEN and p85 mutations found in human tumor samples, and some that we have engineered to prevent p85 from binding to PTEN. We will determine how these mutations impact PTEN regulation by p85, and PTEN biological functions. We will also use the Canadian Light Source to determine several protein structures: for PTEN in its inactive form, for the part of p85 that binds PTEN, and for a complex containing both p85 and PTEN. This will help us better understand the importance of different parts of each protein and the impact of cancer-associated mutations. A better understanding of p85 and PTEN regulation will enable the identification of patients with critical p85 and/or PTEN mutations. As we move to more personalized medicine, it is important to identify the molecular changes present in each patients tumor to identify those most able to benefit from the newly emerging precise targeted treatments directed at components in this pathway.