GTPases are a large family of proteins that perform essential functions in the cell. Members of the Ras superfamily of small GTPases act as binary switches that regulate numerous biological pathways, including cell proliferation, survival, and motility. Mutations in Ras genes lead to tumor development and are found in more than 30 percent of human cancers.These Ras-family GTPases are targets for therapeutic intervention in cancer, but we still don’t know all the details of how they are regulated.
Maurine E. Linder, Molecular Medicine, collaborating with the lab of Hening Lin, Chemistry and Chemical Biology, has identified a lipid modification, reversible lysine palmitoylation, that regulates Kras4A, a Ras isoform that’s broadly expressed in cancer cell lines and human colorectal tumors. They’ve found an enzyme that removes the modification, resulting in increased transforming activity in Kras4A. Based on this exciting discovery, Linder, Lin, and their teams are now determining whether other small GTPases are regulated by the same modification and identifying the mechanism that adds palmitate to lysines in proteins.
The studies will establish a novel regulatory mechanism for the Ras family of small GTPases and provide new insights into their biological function. In addition, the team’s studies will for the first time establish the biological significance of a previously under-recognized modification, lysine palmitoylation. Because Ras-family proteins are considered important therapeutic targets, the studies have the potential to identify new strategies for cancer treatment.
NIH Award Number: 1R01GM121540-01A1