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.