Feb. 27, 2008 Researchers from The University of Texas Health Science Center at San Antonio have determined the atomic-level structure of transforming growth factor-beta (TGF-β), offering clues as to how it interlocks with cell receptors with which it has special affinity. This interaction plays an important role in normal cells but is especially important in cancer.
TGF-β protein-receptor interaction promotes processes such as immune suppression, tissue remodeling and formation of blood vessels that lead to the growth and metastasis of cancer cells. The new finding, reported in the February issue of Molecular Cell, is being called a major milestone in the field and is expected to facilitate development of novel cancer therapies.
“TGF-β acts as a tumor suppressor in normal cells, but in cancer this growth-inhibiting capacity is selectively lost, and in turn TGF-β 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-β 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-β and its receptors. These should block assembly of the TGF-β signaling complex and in turn eliminate TGF-β’s tumor-promoting activities.”
Although there are more than 40 other proteins like TGF-β in humans, none are able to bind the TGF-β receptors and hence none function in the same manner as TGF-β. “TGF-β 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-β 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-β and the TGF-β 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-β.”
Cancer cells produce large amounts of TGF-β compared to normal cells. Many research groups are developing anti-TGF-β therapies to address disease situations in which the tumor-promoting activities are fueled by TGF-β over-expression, Dr. Hinck said. The current research may now allow these therapies to become much more targeted.
The finding drew the notice of a major voice in the TGF-β research field, 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 described how the “very private embrace” of TGF-β by its receptors creates an exquisite “selectivity mechanism that the work of Groppe et al (2008) so beautifully illustrates.”
Dr. Hinck joined the UT Health Science Center in 1997 and has studied TGF-β and its receptors since arriving in San Antonio. The work that culminated in the determination of the TGF-β 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.
The studies were carried out in the Department of Biochemistry at the UT Health Science Center and utilized 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.
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