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UNC scientists block cellular enzyme activity involved in cancer progression

02.06.2004


Scientists at the University of North Carolina at Chapel Hill have found an unexpected way to turn off a cellular enzyme involved in the progression of several types of human cancers.



The enzyme, focal adhesion kinase (FAK), is known to promote cellular movement and survival. Its over-activity promotes cancer cell growth and metastasis. The new study demonstrates for the first time that one segment of FAK called the FERM domain plays a crucial role in activating FAK.

Subtle changes to the FERM domain make FAK activity deficient, the study showed. This discovery raises the possibility that drugs designed to mimic this modification could allow doctors to turn off FAK in cancer patients, UNC researchers said.


The new findings appear in the June 2 issue of the journal Molecular and Cellular Biology. The study’s lead author, Dr. Michael D. Schaller, first isolated FAK in 1992 while searching for proteins involved in transforming normal cells into cancer-like cells. Schaller is associate professor of cell and developmental biology in UNC’s School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center.

"Since FAK was discovered in the context of cancer, there was immediate interest in relating FAK activity to its potential role in the development and progression of tumors," Schaller said.

One way cells sense and respond to their environment is through receptor molecules called integrins, which are located on the cell’s outer surface. FAK relays signals from integrins to other molecules inside the cell that ultimately control the growth, survival and movement of the cell. Because unrestrained growth, survival and motility are hallmarks of tumor cells, the basic biological functions of FAK have implied its involvement in cancer.

Studies continue to connect unregulated FAK activity with malignant cancer, said Schaller. However, no drugs have been developed that are able to specifically inhibit FAK activity.

"If we can figure out the minute details as to how FAK works, then we can determine how to block its activity," Schaller said. "And if we do that, then we might be able to apply what we learn therapeutically against cancer."

To better understand FAK activity, Schaller collaborated with the Structural Bioinformatics Core Facility at UNC to predict the three-dimensional configuration of FAK’s FERM domain.

Computer modeling of the FERM domain predicted a small patch of positively charged amino acids on its surface. These amino acids are conserved in the FAK molecules of organisms as diverse as insects and humans.

Schaller and his colleagues then engineered a mutant FAK molecule devoid of positive charges on that small patch of FERM and found that their mutant protein was nonfunctional. Whereas breast cancer cells responded to increased expression of normal FAK by migrating faster, the mutant FAK was unable to provoke any change in movement from breast cancer cells.

"Our mutant appears to be deficient for turning FAK on and making cells move," Schaller said.

The positively charged region identified in this study seems to cooperate directly with other domains of the molecule, he added.

"Disruption of this interaction might reduce activation of FAK and impair aberrant cell motility or survival conferred by FAK under pathological conditions, such as cancer."


The study was supported by grants from the National Institutes of Health and the U.S. Department of Defense.

By STUART SHUMWAY
UNC School of Medicine

Note: Contact Schaller at (919) 966-0391 or crispy4@med.unc.edu.
School of Medicine contact: Les Lang, (919) 843-9687 or llang@med.unc.edu

L. H. Lang | EurekAlert!
Further information:
http://www.med.unc.edu/

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