Role of the candidate protein methyltransferase METTL18 in cancer biology

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Project Summary Covalent post-translational protein modifications contribute to all aspects of cell physiology and are a primary source of protein functional diversity in mammals. The aberrant regulation of these modifications, as well as the enzymes that generate them, is a common feature of human disease, including cancer. There are more than 150 protein methyltransferases encoded in the human genome, and a growing number of human proteins, including several with established roles in signaling and cancer, are known to harbor functional post-translational methylation events. Most methylation events occur on either lysine or arginine residues; however, our lab and others have recently discovered that histidine methylation occurs on over 200 human proteins as well. Still, very little is known about the molecular, signaling and biological consequences associated with protein histidine methylation. This proposal focuses on a protein histidine methyltransferase (PHMT), METTL18, and its role in cancer. In preliminary work I found that METTL18 methylates the ribosomal protein rpL3 at position His245 in numerous cell lines and mouse tissue. I also have evidence that METTL18 regulates protein synthesis and oncogenesis. Here I propose to use multi-disciplinary approaches, including biochemical, proteomic and cell biological strategies to (1) investigate the molecular and biological function of METTL18 catalytic activity and (2) characterize the physiologic role of METTL18 in gastric cancer. The proposed project will be executed in the laboratory of Dr. Or Gozani at Stanford University. Dr. Gozani is an experienced mentor and a leader at the intersection of the fields of protein methylation and cancer biology. He and the Stanford University Department of Biology are well-suited to support my research project and graduate education.