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Clues to the Mystery of Disease

Researchers at the University of North Carolina School of Medicine have devised a new biochemical technique that will allow scientists to delve much deeper than ever before into the specific cellular circuitry that keeps us healthy or causes disease.

The method, developed in the lab of Klaus Hahn, PhD and described in the journal Nature Chemical Biology, helps researchers study how specific proteins called kinases interact to trigger a specific cellular behavior, such as how a cell moves. These kinase interactions are extraordinarily complex, and their interactions remain largely unknown. But researchers do know that kinases are crucial operators in disease.

A release from the university quotes Hahn as saying, "I dare you to find a disease in which kinases are not involved. These kinase processes have been very difficult to fully understand, but we all know they're very important."

For years, scientists have been able to tweak a kinase to see what would happen – such as causing cell death or cell movement or cellular signaling. But these experiments can only scratch the surface when it comes to understanding the cascade of kinase interactions that lead to a cellular behavior. Nor have these experiments been able to show the timing of rapid events. That's important, Hahn said, because when a protein is activated has a lot to do with how the cell will respond. Drug developers haven't been able to take this into account, which is probably one reason why some drugs that target proteins don't work as well as scientists had hoped.

"Imagine you're an electrician looking at a circuit board, and all you can do is plug something in and watch all the circuits light up, but you have no idea how the board really works," Hahn said. "What you'd like to do is put a probe on one component, turn it on, and see what immediately happens to the circuit components next to that one component."

If you could do this with all the circuit components, then this would allow you to learn how the circuitry is built.

"We are now doing this in live cells and seeing what happens," said Hahn, a member of the UNC Lineberger Comprehensive Cancer Center. "Kinases are the circuit components. And we can now activate just one kinase and study how it interacts with just one other molecule in real time."

These kinase circuits are critical for cellular activities, such as metabolism, signaling, protein regulation, movement, enzyme secretion, and many others. All kinases have nuanced differences but all of them share one little part that researchers call a domain.

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