Andrew P. Hinck, Ph.D., professor in the Department of Biochemistry, is the first to see how the ‘puzzle pieces’ fit together to make TGF-beta work.
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Contact: Will Sansom, (210) 567-2579

SAN ANTONIO (Feb. 22, 2008) — Researchers from The University of Texas Health Science Center at San Antonio have for the first time identified the complex structure of a protein, called TGF-beta, bound to its specific target on the surface of cells. This interaction between the protein and its target plays an important role in normal cells, but when it goes wrong, it can play a critical role in the growth and spread of many cancers.

The finding has been hailed as a major milestone and is expected to bring about the development of new targeted cancer therapies.

Interactions lead to growth and spread of cancer
TGF-beta interlocks like an intricate puzzle with receptors on the surface of cells. This interaction promotes processes such as immune suppression, tissue remodeling and the formation of blood vessels that lead to the growth and spread of cancer to other areas of the body. The new finding is reported in the February issue of Molecular Cell.

This illustration shows the complex interaction of the ‘puzzle pieces’ of the TGF-beta protein with its receptors.

New knowledge opens door to novel treatments
“TGF-beta acts as a tumor suppressor in normal cells but in cancer, this growth-inhibiting capacity is selectively lost, and in turn TGF-beta becomes a bad actor that induces many activities that lead to the growth and metastasis of cancer cells,” said corresponding author Andrew P. Hinck, Ph.D., professor in the Department of Biochemistry at the UT Health Science Center. “Understanding the detailed nature of the interactions between TGF-beta and its receptors represents a critical new step forward, as this opens up the opportunity of finding new drugs that mimic the interactions between TGF-beta and its receptors. These should block assembly of the TGF-beta signaling complex and in turn eliminate TGF-beta’s tumor-promoting activities.”

Protein is unique in its way of interlocking with receptors
Although there are more than 40 other proteins like TGF-beta in humans, none are able to bind to the TGF-beta receptors, so none of them function in the same way. “TGF-beta is very selective in its interactions with its receptors, due to the fact that four receptor subunits bind in an interdependent manner, interacting not only with TGF-beta but with one another as well. It is like a tight-fitting jigsaw puzzle that only goes together one way,” Dr. Hinck said.

“Although it was not previously appreciated by the broader scientific community, our results definitively demonstrate that TGF-betaand the TGF-beta receptors are very unique relative to related factors and their receptors,” he said. “In particular, other factors of this protein family bind their corresponding receptors independent of one another and without direct contact. This is fundamentally important since there are fewer constraints in terms of how the puzzle pieces fit together and, as such, these factors tend to ‘fit’ a much broader range of receptors compared to TGF-beta.”

New evidence may promote new targeted therapies
Cancer cells produce large amounts of TGF-beta compared to normal cells. Many research groups are developing therapies to counteract the overproduction of this protein in cancer cells, Dr. Hinck said. Having a better understanding of how TGF-betainteracts with its receptors will allow researchers to develop more effective therapies targeted to this protein interaction.

The new finding drew the attention of a major TGF-beta researcher, Joan Massagué, Ph.D., of the Howard Hughes Medical Institute and Memorial Sloan-Kettering Cancer Center in New York. In a preview of the work published in the same issue of Molecular Cell, Dr. Massagué said the “very private embrace” of TGF-beta by its receptors creates an exquisite “selectivity mechanism that the work of Groppe et al (2008) so beautifully illustrates.”

Dr. Hinck joined the Health Science Center in 1997 and has studied TGF-beta and its receptors since arriving in San Antonio. The work that culminated in the determination of this protein-receptor complex was carried out by Jay Groppe, Ph.D., a research assistant professor who previously carried out structural studies of other related molecules at the Salk Institute of Biomedical Sciences in La Jolla, Calif. “Jay’s efforts were critical to the successful completion of this project; a lot of the credit goes to him,” Dr. Hinck said.

Dr. Hinck is the first to see how the ‘puzzle pieces’ fit together
Bruce Nicholson, Ph.D., professor and chairman of the UT Health Science Center Department of Biochemistry, said, “No one up to now has been able to resolve the structure of TGF-beta complex with its receptors, as this requires the precise assembly of several subunits or components — the ‘puzzle pieces’ as Dr. Hinck calls them.”

The studies were carried out in the Department of Biochemistry and used the resources of the X-ray Crystallography Laboratory, which is directed by P. John Hart, Ph.D., and the Center for Surface Plasmon Resonance, which is directed by Eileen Lafer, Ph.D.

Dr. Hinck is a professor of biochemistry and an investigator in The Cancer Therapy & Research Center (CTRC) at the UT Health Science Center. The work was funded by awards to Dr. Hinck from the National Institutes of Health and the Robert A. Welch Foundation. CTRC, the Department of Biochemistry and the Office of the Vice President for Research at the Health Science Center helped fund the core research facilities that made this work possible.

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