Key Player in Lymphocyte Differentiation Discovered; Promotes Metastasis

TOPLINE

  • DEF-binding pocket (DBP) of extracellular regulated kinase (ERK) regulates the differentiation of lymphocytes
  • Since DBP also promotes metastatic spread of tumor cells, blocking this site could hobble tumors while letting ERK function normally

In order to mature into functional lymphocytes, stem and progenitor cells depend on receptors that pick up subtle changes in the cellular environment and relay that information to the nucleus, which turns the right genes on and off. And that’s where things can get complicated.

“Receptors rarely encounter all-or-nothing situations, and instead they have to interpret shades of gray,” says Fox Chase researcher David L. Wiest, PhD. “Think of the receptors as 100-watt bulbs with three settings—dim, medium, or bright—that can burn at those different levels for different lengths of time. Then, in response to those differences, the cell reacts. But how does the cell know when the bulb is dim, medium, or bright, or on for a short or long time?”

Now, Wiest and his colleagues have uncovered one major clue in the differentiation of lymphocytes. They found that the molecule in the cellular relay system that is central to the cell’s ability to interpret differences in the intensity and duration with which the “bulb” burns is extracellular regulated kinase (ERK)—specifically a little-known binding site called the DEF-binding pocket (DBP).

When the researchers disabled the DBP of ERK in the blood cells of mouse embryos, leaving ERK otherwise intact, they found that the mice survived but lacked γδ T cells. Alternatively, when they knocked out the D-domain—the main binding site of ERK that carries out most of ERK’s functions—γδ T cells developed normally. The researchers found that the DBP enables ERK to bind to a distinct set of proteins that specify the fate of γδ T cells.

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ERK2 is a signaling molecule that helps relay information from the outside of cells to the cell interior in two ways. It uses the “D-domain” (green) to relay information from signals that are shorter in duration and the “DEF-binding pocket” or DBP (yellow) to relay information from signals of increased duration. These capabilities are on opposite faces of the molecule, enabling one to selectively sever them to manipulate the cellular outcomes produced by information received from the cell exterior.

The results, published in the December issue of Immunity, aren’t just relevant to normal cells. The DBP of ERK also plays a critical role in promoting metastatic spread of tumor cells.

In order for tumor cells—of epithelial cancers—to leave their current site and spread throughout the body, they have to undergo a form of differentiation, explains Wiest, transitioning from a basic epithelial cell to a motile fibroblast. The DBP of ERK is key to this process. “Although we didn’t test whether the mice with disabled DBPs were more resistant to cancer, we believe this to be the case.”

There are drugs that stop ERK from functioning altogether, but since ERK is involved in many cellular processes, totally disabling it is associated with many side effects. Ideally, a new therapy would exploit drugs that selectively block the DBP site of ERK, thus preventing tumor cells from metastasizing while allowing ERK to retain other functions, suggests Wiest. “The next step is to identify such drugs.”

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David L. Wiest, PhD

Sang-Yun Lee, PhD, Francis Coffey, PhD, Shawn P. Fahl, PhD, Suraj Peri, MSc, PhD, Michele Rhodes, Kathy Q. Cai, MD, PhD, and Dietmar J. Kappes, PhD, from Fox Chase, as well as Michael Carleton, PhD, from Rosetta Inpharmatics and Presage Biosciences, Stephen M. Hedrick, PhD, from the University of California San Diego, Hans Jörg Fehling, PhD, from the University Clinics Ulm in Germany, and Juan Carlos Zúñiga- Pflücker, PhD, at the University of Toronto in Canada.