Sometimes, finding out how proteins interact with each other, trigger other reactions and affect development is more complicated than the biochemical process itself. Such was the case for two cancer biologists from Columbia University, New York. While Antonio Iavarone and his colleague Anna Lasorella were exploring the role of a family of proteins in brain cancer, their research led them from gene expression to basic cell-division processes, and on to neurobiology. During the course of this journey, which is detailed on page 471, they collaborated with two separate groups, eventually learning that a family of proteins essential to the basic processes of cell proliferation and cancer also exerts influence beyond cell division in nervous-system development.

Iavarone and Lasorella had been studying a family of proteins to find out whether they were turned off or on during brain development and in brain cancer. These proteins, particularly one known as Id2, were already known to prevent stem cells from differentiating into adult cells. But the experimental data showed a paradox. Id2, which had been thought to be an inhibitor, actually seemed to be stimulating the development of axons — slim fibres that carry signals from nerve to nerve. “We couldn't figure out what it meant,” says Iavarone. “We had the result for a year without really knowing how to follow it up.”

Meanwhile, Lasorella and Iavarone had been using proteomics to identify the partners of Id2 in neuronal cells. They discovered that Id2 interacts with the anaphase promoting complex (APC), a cluster of proteins that works by priming other proteins for degradation and is key to the cell-division process of mitosis. “We looked for how the proteins in the APC complex talked to each other, how they attached to each other and which proteins in APC attached to Id2,” says Iavarone.

With the help of a cancer-biology group at New York University (NYU) that had expertise in looking at biochemical processes triggered by APC, Lasorella and Iavarone found that when APC links up with Id2, the complex then degrades the protein. But when mutations that prevented binding to APC were introduced in Id2, the protein became resistant to degradation and accumulated inside the cells at very high levels.

Meanwhile, a paper from a group at Harvard Medical School assigned a new function to APC in mature neurons, the ability to prevent axon growth. But the paper didn't explain the exact mechanisms. With a hunch that Id2 might play a role, Lasorella and Iavarone collaborated with the Harvard group. They showed that the mutated 'super Id2' protein allows axons to grow in different types of neurons, even in the presence of the myelin components that normally coat nerves and prevent them from regenerating after injury.

“This was a very exciting journey,” says Iavarone. “We moved from finding Id2 as a target of the APC to showing there are APC–Id2 complexes in neurons, and we discovered how all of this happens.” The path taken by these researchers, from looking at a protein complex associated with cell division to finding out how the same complex can affect axonal growth, shows how simple problems in molecular biology can turn into long, unexpected trips.