Cell Talk

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by Neil Caudle

Resolving the complexities of cell signaling is impossible for any one scientist or lab, so researchers collaborate, often with colleagues all over the world. But more and more frequently these days, Der is also finding partners here at home. Recently, he began working with John Sondek, a newcomer in pharmacology who specializes in studies of the structure of signaling molecules.

"Structure becomes critical when there are several molecules that are closely related," Der says. "Let’s say you have three molecules, A, B, and C. A is the critical one, the one involved in cancer. So we want to make an inhibitor against A. But because B and C are similar, there’s a good possibility that the inhibitor might recognize B and C. So John Sondek’s lab might, for example, look at the structures of the inhibitor and its potential targets. A drug sort of fits a pocket. Each pocket is a little different. The more precisely you can design that drug so that it recognizes a specific pocket, the more likely you’re going to be able to make a drug to target protein A but not B and C."

Sondek and David Siderovski, another newcomer in pharmacology, are in demand as research partners because their work bridges various kinds of cell-signaling studies, engaging the team in what Ken Harden calls "crosstalk."

Until recently, the signaling pathways explored by cancer researchers like Der and Earp—pathways having to do with cell growth and regulation—didn’t seem directly involved with the hormone-and-neurotransmitter signaling that Harden and others pursued. Sure, the two groups have always spoken the same language, but now they are part of the same conversation.

"We’re finding that these two areas connect in a lot of very interesting ways," Harden says. "And these new guys, John Sondek and David Siderovski, are right in the middle of the crosstalk. So is Henrik Dohlman, recently recruited from Yale by David Lee, the chair of biochemistry."

Dohlman, Siderovski, and others independently discovered a class of signaling molecules known as RGS proteins, which help regulate the on-off switches in various signaling pathways. These RGS proteins are part of the crosstalk. They are also evidence of just how deep the mysteries of cell signaling can run.

Take the case of RGS2, for instance. Siderovski has found that RGS2 affects the immune system by telling T cells how fast to launch a defense against invaders. When he studied mice in which RGS2 had been genetically "knocked out," Siderovski found that their immune responses slowed dramatically.

This in itself was intriguing. But then the results took an astonishing turn. The knockout mice, which looked normal and displayed normal cognitive and motor skills, were remarkably anxious and fearful. They avoided light, backed down from confrontation, and were bullied by their normal brothers. Why would a protein involved in the regulation of immune response also affect fear and aggressive behavior?

"We don’t know," Siderovski says. "We have seen that RGS2 controls an anxiety-aggression circuit in the brain, but now we need to swim upstream and find out what receptor is firing too often in the brains of these knockout mice. If we can piece together the molecular reasons for this behavioral deficit, we might have another avenue to develop new antianxiety drugs."

Most likely, this quest will begin where his others have—with Siderovski staring at protein sequences on a computer screen, trying, as he puts it, to read the tea leaves. "I always say that my hypotheses are generated in silicon, rather than in the test tube," he says. "And then we’ll go to the bench, purify the proteins, put them in neurons, make a knockout mouse, and do what we have to do to test our hypotheses. But they all start with this new explosion of bioinformatics."

So Siderovski has been cast as the data guy, Sondek as the structure guy. And both of them believe that Rudy Juliano, their chair in pharmacology, had a design, a strategy in mind when he recruited them. More than individual talents, they work as complements, a team greater than the sum of its parts.

Siderovski has a favorite example. He and Sondek had been using a computing technique to delve into the genome, trying to find binding partners—places where signaling molecules connect—for two proteins they had been studying. "And there were hits," Siderovski recalls. "But they were reported as being statistically insignificant, as being in the noise. So John and I went back to the literature, and we jogged back and forth. And this is the beauty of this collaborative place: we kept talking about it. And we finally teased out a deduction that both of our molecules bind to the Ras molecule, which is, as Channing Der will tell you, a central oncogene."

It was a hunch that paid off, and it was one they might not have been free to follow, somewhere else. Siderovski, who worked several years in industry, jumped back into academia because, he says, he felt passionate about RGS proteins and wanted to pursue them on his own terms.

"In industry, the shareholders can’t wait," Siderovski says. "But here, we can have a longer-term vision. If we work on basic research for five years, we might come up with ten drug targets, each of which could save lives and generate a billion dollars. Because here, the National Institutes of Health and the people of North Carolina are making the investment."

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