Volume 2, Issue 14 September 2005
Mapping Cellular Signals
UC Berkeley professor Kevan Shokat is a chemist who thinks like a biologist. He's developing chemical tools to understand and manipulate the complex communications system at the heart of every cell. Eventually, his research could lead to a pharmacological map of the human cell that would guide the rapid development of new drugs to combat diseases like cancer and diabetes.
Kevan Shokat is also a researcher with the California Institute for Quantitative Biomedical Research (QB3) (Majed photo)
"We look for biological questions that genetics and biochemistry can't easily answer and think of chemical tools to get at them," says Shokat, who is also a professor of cellular and molecular pharmacology at the University of California, San Francisco, and affiliated with the Howard Hughes Medical Institute.
Shokat's laboratory focuses on kinases, enzymes that transfer energy stored within the cell to other proteins. The kinases act as control switches for many cellular activities, from development to death. However, with more than 500 kinases in every cell, identifying a specific kinase's functionality and manipulating it without affecting others in the protein family is no easy task. The pay-off could be huge though.
"The ability to understand how a specific kinase regulates signaling pathways would permit the development of new drugs and new strategies to control almost all disorders including cancer, neurological disorders, autoimmunity, and tissue rejection," he says.
For example, Shokat explains, inhibiting a particular kinase in a cancer cell could stimulate the death of that cell. On the other hand, simultaneously knocking out another kinase could result in dangerous side effects. To help understand each kinase's role in the cell, Shokat developed a chemical-genetic tool to selectively mutate kinases so that they can be individually switched on and off by introducing a drug into the body.
"It's like we changed the lock on the switch that turns the kinase on or off and now we have the key to it," he says. "So we can determine whether inhibiting that kinase is going to stop the spread of cancer, for example, or cause the animal to lose weight, indicating that it's not a good target for therapy."
This looped animation shows the engineering of the active site of a protein kinase to introduce a new active site pocket (red) that can be accessed by a tailor-made inhibitor molecule (grey and blue). (courtesy Daniel Rauh/Shokat Laboratory)
Already, Shokat and his colleagues are mutating and testing more than one hundred kinases. Their aim is to identify the kinases that may be tied to asthma, diabetes, cancer, neurological disorders, and even drug addiction. The technique is generic in that it can inhibit any of the mutated kinases they're studying with little modification.
"If inhibiting a mutated kinase affects a disease in the way we hope, a pharmaceutical company could then make an inhibitor for the wild type form of the kinase as it exists in the body," he says.
In April, Shokat and two collaborators demonstrated that their chemical-genetic technique could also shed light on how cells in the brain develop. Understanding how the growth of neurons are regulated could provide insight into diseases like Alzheimer's, Shokat says.
"Kinases are involved in almost every aspect of physiology," he says. "Yet people have no idea about the function of even the most well-studied kinases."
To that end, Shokat is also perfecting another chemical-genetic tool similar to the inhibitor approach that can reveal kinase function. Instead of targeting a mutated kinase with an inhibitor, a "tagging" molecule is delivered to the kinase. Shokat can then track the kinase as it travels along the signal pathways in the cell.
"The first tool allows us to inhibit the kinase and see what function gets regulated, but with this approach we can watch all of the dynamic changes inside the cell," Shokat says. "Our ultimate goal is to link the two together."
Shokat hopes that someday, scientists wielding his chemical-genetic tools will build a map of all the kinases in the cell. Pharmacologists could then consult that map to determine the best drug therapy to fight a particular disease.
"We have the map of the human genome," Shokat says. "But we'd love to know the effect of inhibiting any human protein and link that to a disease. It's all about understanding biology in the context of chemistry."