The discovery of an intracellular homing system that guides a cancer-causing protein called K-Ras could help in the fight against some of the world’s deadliest cancers, report scientists at McGovern Medical School.
The research appears in the journal Cell.
Cancer-causing mutations in the K-Ras protein are found in approximately 20 percent of human tumors, including cancers of the lungs, pancreas and colon. These three types are responsible for nearly 250,000 deaths in the United States annually. Currently, no effective treatments directly inhibit K-Ras, which works as a molecular switch that normally helps the body replace cells as they die off. Mutations in K-Ras lock the switch in the ‘on’ position, leading to uncontrolled cell growth and cancer.
In order to work, K-Ras must bind to the plasma membrane of the cell. “We’ve known for 25 years that the membrane anchor located at one end of K-Ras is positively charged. Since the plasma membrane is negatively charged, we all believed that K-Ras anchoring was simply a matter of opposite charges attracting each other. Amazingly what we have now discovered is that the K-Ras anchor actually operates as a highly sophisticated ZIP code that seeks out very specific lipids on the plasma membrane,” said John F. Hancock, M.B, B.Chir., Ph.D.,Sc.D., the study’s senior author and chair of integrative biology and pharmacology.
“If we mess with the sequence of the ZIP code, we misdirect K-Ras to the wrong lipids on the plasma membrane, just like mail being sent to the wrong city or state if the ZIP code is misspelled. Importantly, when K-Ras is misdirected in this way, its ability to function is severely compromised,” said Yong Zhou, Ph.D., the study’s lead author and assistant professor of integrative biology and pharmacology.
“This paper gives us a new perspective on how we see the K-Ras protein,” said Alemayehu Gorfe, Ph.D., the paper’s co-senior author and associate professor of integrative biology and pharmacology. “At this point, the discovery is still basic science, but it allows us to think about K-Ras in a totally different way and opens up new strategies for designing anti-K-Ras drugs.”
Deciphering the K-Ras “ZIP code” and figuring out exactly how it works required the combined expertise of Hancock and Gorfe’s teams using high-resolution electron microscopy and sophisticated computer simulations. Their McGovern Medical School collaborators included Priyanka Prakash, Ph.D., Hong Liang, M.D., and Kwang-Jin Cho, Ph.D.
The study, titled “Lipid-sorting specificity encoded in K-Ras membrane anchor regulates signaling output,” was supported by the Cancer Prevention & Research Institute of Texas (RP130059), National Institutes of Health (R01GM100078, K99-CA188593), Texas Advanced Computing Center and Extreme Science and Engineering Discovery Environment (MCB150054).
Hancock and Gorfe are on the faculty of the Graduate School of Biomedical Sciences, which is a partnership of UTHealth and The University of Texas MD Anderson Cancer Center. Hancock is the vice dean of research and the John S. Dunn Distinguished University Chair in Physiology and Medicine at McGovern Medical School.