Grant: CIHR New Investigator

The human body is composed of billions of cells, and these cells in turn are composed of thousands of proteins that work together in complexes and networks to carry out all cellular functions. One important function is "programmed cell death", or the triggering of cells to die at a particular point in their life cycle. In cancer cells, it is this programmed cell death that is disrupted, allowing them to continue growing and dividing. A major mechanism that regulates protein function in cells is the reversible addition of phosphate groups (protein kinases add them while protein phosphatases remove them). Abnormal phosphorylation has been linked to the progression of certain types of cancer, and my laboratory studies the targeting of protein phosphatase activity within living cells to better understand the phosphorylation-mediated processes that give rise to cancers in humans. These processes can then be targeted for disruption in therapeutic approaches. We have developed a unique fusion of techniques that combines imaging of fluorescent phosphatases in live cells with recovery of these phosphatases and identification of all of the proteins with which they associate. Using this approach we identified RepoMan, which specifically directs protein phosphatase 1 (PP1) activity to proteins associated with DNA. RepoMan is highly expressed in certain aggressive tumor types, suggesting that it is suppressing systems that regulate programmed cell death. Indeed, reducing levels of RepoMan in cells led to rapid and massive cell death. In order to exploit the therapeutic potential of RepoMan in the treatment of certain cancers, we must gain a better understanding of its mode of action. These studies will aid the design of drugs that target specific phosphatase complexes involved in cell survival, to provide more efficient treatment of certain types of cancer.