December 2001

From University of Texas Southwestern Medical Center at Dallas

Scientists describe structures of protein molecules that enable two-way signaling between cells

Two neuroscientists from UT Southwestern Medical Center at Dallas collaborated with cancer investigators in New York and Australia to determine the structures of protein molecules that bind together to initiate two-way signaling between human cells.

The study, published in today’s issue of Nature, was built upon an earlier groundbreaking discovery by Dr. Mark Henkemeyer, assistant professor in UT Southwestern’s Center for Developmental Biology, and his associate Chad Cowan, a doctoral candidate in the UT Southwestern Graduate School of Biomedical Sciences who won the school’s top student award for research last year.

They described the molecular details of how neurons sense their environment as they project their fibers to distant locations in the body. This finding was reported in a September issue of Nature.

Now, a team from the Memorial Sloan-Kettering Cancer Center in New York, in collaboration with Henkemeyer, has derived three-dimensional picture of the molecules that mediate this novel cell-to-cell communication system. The molecules are called Eph and Ephrin proteins.

“The genome DNA sequencing project tells us what the amino acid sequence of the proteins are, but it doesn’t give us the structure or shape that the proteins take after they have folded up as they’re activated to do their jobs,” Henkemeyer said. “Now we can visualize at atomic-level resolution how these important molecules interact to initiate bidirectional signaling between cells.

“The cancer investigators are interested in Ephs and Ephrins because these same proteins also play similar communication roles in many other moving, remodeling cells, including vascular endothelial cells and, potentially, migrating metastatic cancer cells. These bidirectional messages or signals appear to help control how cells move and interact as the nervous system and other organs develop in the embryo or perhaps as cancer cells move throughout the body.”

To describe the structures of the Eph and Ephrin interactions, the researchers first purified both molecules in their interactive form and then grew crystals of the proteins, Henkemeyer said. Then they subjected the crystals to X-ray diffraction analysis to determine their shape. The analysis of the results yielded a picture of how specific domains of the proteins can interact to then send reciprocal messages into their resident cells.

“If further research confirms that metastatic cancer cells also move throughout the body by using the same biochemical pathways, then it may be possible to use these three-dimensional structures to formulate compounds to inhibit, interrupt or otherwise alter the Eph-Ephrin signals and, thereby, effect new cancer therapies,” said Henkemeyer. “The groundwork has already been laid in that direction.”

For neuronal cells, Henkemeyer said, the goal would likely be to stimulate or inhibit the Eph-Ephrin pathways and perhaps accelerate nerve regrowth and regeneration as therapies for brain or spinal-cord injuries.

Drs. Dimitar Nikolov and Juha-Pekka Himanen were the structural study’s lead researchers in cellular biochemistry and biophysics at Memorial Sloan-Kettering. Also participating were scientists at the Brookhaven National Laboratory in New York and the Ludwig Institute for Cancer Research at the Royal Melbourne Hospital in Australia.

The protein structural study was supported by the National Institutes of Health, the New York Council Speaker’s Fund for Biomedical Research and the Welch Foundation.

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