The University Record, March 15, 1999
News and Information Services
|1999 Russel Lecturer Jack Dixon (left) with President Lee C. Bollinger prior to Dixon's address on phosphatases. Photo by Bob Kalmbach|
Until the late 1980s, little was known about how these phosphatases work together with their better-understood counterparts-the enzymes called kinases. Collectively, the phosphatases and kinases act as a set of molecular switches to turn cells on and off. Much of our current understanding of phosphatase function comes from work by Dixon and his research associates in the Department of Biological Chemistry.
In recognition of the quality and significance of this work, Dixon was chosen to present the U-M's 1999 Henry Russel Lecture last week, which he titled "Playing Tag with Death: A Biochemist's View of the Plague, Cancer and Signal Transduction." The Henry Russel Lectureship is the highest honor a senior faculty member can receive for distinction in research. A U-M faculty member since 1991, Dixon is the Minor J. Coon Professor of Biological Chemistry and department chair.
The cellular activation-deactivation process Dixon studies is so central to a cell's ability to respond to environmental signals that it has been "like discovering the telephone system," he says. Understanding the biochemistry of cellular signaling could lead to new drugs to treat cancer, infectious diseases and diabetes.
Basically, the process works like this: To turn cellular activity on, an enzyme called a protein tyrosine kinase attaches or "tags" a phosphate molecule to a specific amino acid in the cell. To turn cellular activity off, another enzyme called a protein tyrosine phosphatase removes or "snips off" the phosphate molecule. Dixon has focused on identifying and understanding the phosphatase family of enzymes.
One of the first problems he tackled was determining which of the hundreds of amino acids in a phosphatase enzyme were the key players in removing the phosphate "on switch" from the cell. Dixon and his colleagues finally narrowed it down to a string of just 10 amino acids.
"These 10 amino acids were the key-the active site of the phosphatase enzyme," Dixon said. "If we changed even one amino acid, the protein was dead and there was no activity. So we decided the best way to find other phosphatases was to search for proteins with this same molecular fingerprint."
The search led in an unexpected direction. "We found one bacterial protein with the same fingerprint," Dixon said. "It was in Yersinia pestis-the bacteria responsible for the plague or "Black Death" that killed 20 million people in Europe during the Middle Ages." Since then, other scientists have discovered similar phosphatases in other bacterial pathogens like Salmonella, Dixon added.
During the 200 million years or so that bacteria have co-existed on Earth with mammals, pathogenic bacteria like Yersinia, Salmonella, Shigella and E. coli have developed the ability to inject a phosphatase and a few other bacterial virulence factors into mammalian cells. When these proteins enter a mammalian cell like a macrophage, they can rapidly disable the immune response.
"These bacteria use the phophatase as a lethal weapon, and they are incredibly fast and effective," Dixon said. The Yersinia phosphatase can enter a macrophage- the immune system's first line of defense against invading organisms-and disable the cell before it can call for reinforcements from other immune cells.
In 1997, a new phosphatase called PTEN, which works like a tumor suppressor gene, was identified. Although PTEN resembled other phosphatases, it was not clear how it carried out its function as a tumor suppressor. Dixon's lab was the first to demonstrate that PTEN functions in a novel manner. Its job is to turn off one specific lipid molecule that activates a kinase known as Akt. "By preventing the prolonged activation of Akt, PTEN prevents cancer development," Dixon said.
Dixon estimates that there are about 500 phosphatases in the human genome; only about 100 have been identified so far. Some phosphatases function to guide developing neurons to their targets, some initiate cell division, and the function of others remains unknown. It leaves Dixon and his research team with a lot of work ahead of them.
"I look forward to coming to the lab every day," he said, "to see what new and exciting secrets nature has to share with us."