Grant: Project Grant

Proteins are essential for all processes in our cells. Some proteins can be modified by the repeated addition and removal of a fatty molecule called palmitate. This process, termed the "palmitoylation cycle", helps direct these proteins to parts of the cell where they are needed to carry out their roles. One target of palmitoylation is NRAS, which is a protein that can promote the development of cancers such as leukemia and melanoma. By interrupting the NRAS palmitoylation cycle, we may be able to block the growth of cancer cells. We understand quite a lot about how palmitate is added to proteins, but much less about how it is removed. Until recently, researchers had identified only two enzymes - known as APT1 and APT2 - that can remove palmitate from proteins. My lab showed that APT1 and APT2 are not needed to remove palmitate from NRAS or from a brain protein called PSD95. Instead we discovered another enzyme called ABHD17 that does remove palmitate from NRAS. A drug against ABHD17 might stop the cancer-causing activity of NRAS by blocking its palmitoylation cycle. Before we try to develop such a drug, we first need to find out if ABHD17 acts on other proteins in cells and, if so, which ones. We also want to understand what makes ABHD17 specific for some proteins but not others, and how its action on NRAS is controlled. Cells have three different types of ABHD17 enzymes, so it will also be important to know if we can target just one form of the enzyme, or if we need to inhibit all three. This project will help establish if ABHD17 is a good target for future drug development. If so, the longer-term challenge will be to develop specific chemicals that inhibit ABHD17 activity and test if they can treat cancers such as leukemia and melanoma.