Saccharomyces cerevisiae has been widely studied and was the first eukaryote to have its genome fully sequenced. What makes this microbe a great research tool is that, although it is simpler than higher eukaryotes, its basic mechanisms of cellular function are the same as those of plant and animal cells, despite a billion years of divergent evolution.
Stone, an associate professor of biological sciences, and Metodiev, a research assistant professor, specialize in signal transduction — the processes whereby cells consider the many thousands of stimuli they encounter and turn this information into the responses necessary for life. Stone began his study of yeast signal transduction in 1988.
The yeast exists as two mating types, like opposite sexes. Each mating type proliferates rapidly when grown in separate cultures, but when mixed, the opposite types communicate by secreting a chemical love potion called a pheromone. Exposure to pheromone causes the cells to stop dividing, then fuse, or mate.
"To us, the two most important aspects of the mating response are that first, pheromone triggers cells to stop dividing. Second, the cells are able to orient their growth toward the source of pheromone, a process called chemotropism," said Stone. "Growth control is of obvious importance because of its relationship to cancer. Chemotropism is of fundamental importance because we find many chemotropic phenomena in development in adult organisms. For example, our immune systems respond to chemical signals. Whenever we get a wound, immune cells detect the source of chemical signals coming from the wound and migrate toward it. Chemotropism is also relevant to cancer because tumor cells metastasize in response to chemical signals released by specific tissues."
At the molecular level, the yeast mating response works through a series of steps: the signaling pheromone binds to a receptor on the cell membrane, thus activating a signaling molecule called a G-protein. G-protein is made of two parts, G-alpha and G-beta-gamma. G-beta-gamma triggers a sequence of signals along a pathway of enzymes, ending in the activation of a protein called a MAPK, which enters the cell nucleus and affects targets that block cell division.
To resume division, the cells must turn off the mating signal. Exactly how this worked was unclear until Metodiev and Stone, using a research technique called proteomics, discovered that the other part of the G-protein (G-alpha) eventually bypasses this linear signal progression and binds directly to the bottom-level MAPK. It then diverts the MAPK from the nucleus, which allows the growth signal to turn back on. This G-alpha/MAPK binding was previously unknown.
The UIC scientists also discovered that G-alpha lures the MAPK enzymes to the cell's plasma membrane where it works to help orient cell growth toward another cell's chemical signal.
"In contrast to traditional therapies, today's modern drug discovery process is directed at specific proteins and protein-protein interactions," said Metodiev. "In this case, we have demonstrated the interaction of two very important and well-characterized signaling molecules, G-alpha and MAPK. This interaction is a natural target of drug discovery research."
"It's basic scientific research but definitely has the potential to influence therapeutics," said Stone. "There are many human diseases related to problems in controlling cell growth and differentiation. For example, if we know that the metastasis of cancer cells depends on a particular protein-protein interaction, we may be able to develop molecules that block this interaction, and thereby prevent the invasion of healthy tissues."
With further work, Stone and Metodiev hope to determine whether the mechanisms they uncovered in yeast cells operate in human cells. There is evidence suggesting that they do.
The American Cancer Society and the National Science Foundation supported the research.
Princeton University biologists Dina Matheos and Mark Rose contributed to the research for this paper.
Journal
Science