Compound reveals new link between signaling protein and cell migration

September 26, 2005

University of Illinois at Chicago researchers report that a protein that regulates key signaling pathways in cells also plays a role in controlling the active movement or migration of cells. The finding may suggest new pharmaceutical therapies for treating a variety of diseases, including cancer.

The protein, known as Raf Kinase Inhibitor Protein, or RKIP, controls activity of kinases, a type of enzyme that acts as a key component in the biochemical signaling pathways responsible for determining almost all cellular activity. But RKIP's own activity is inhibited when a small molecule organic compound called locostatin, discovered earlier by UIC researchers, binds to it.

Lead investigator Gabriel Fenteany, assistant professor of chemistry at UIC, reports the finding in the Sept. 26 issue of the journal Chemistry and Biology.

The researchers used an approach sometimes called "forward chemical genetics" whereby they first identified locostatin as an inhibitor of cell migration, then used locostatin itself as a kind of bait to fish out the protein to which it binds. That protein was RKIP.

"We have implicated this protein in controlling cell migration, a role it was not previously known to play," said Fenteany. "It's a molecular target of locostatin. We found this on the basis of the chemical affinity of locostatin for this protein."

As a regulatory protein, RKIP controls the functions of kinases, thereby governing signaling pathways. When these pathways are not properly controlled, all kinds of diseases can result, including cancer.

Fenteany and his team also confirmed that RKIP is involved in cell migration by using other methods.

"After finding that locostatin targets RKIP, we wanted to verify that RKIP really does control cell migration," Fenteany said. The researchers removed, or knocked down, RKIP in the cell using a method called RNA interference and looked at the effect on cell migration. They did the opposite manipulation as well -- artificially increasing the amount of RKIP in the cell and again looking at the effect on cell migration. In each case, the result was consistent with RKIP having an important, positive role in the control of cell migration.

"The interest in RKIP now is that it is a new and apparently important modulator of cell migration and therefore a possible target in anti-cancer strategies focused on limiting tumor angiogenesis and metastasis," Fenteany said.

More investigation on how exactly RKIP controls cell migration is needed, Fenteany said. UIC researchers are also trying to determine the potential of locostatin as a drug by looking at its effects on different types of cells and tissues.
-end-
Fenteany's team included UIC chemistry graduate students Shoutian Zhu and Kevin Mc Henry. Zhu purified the RKIP, analyzed the effect of locostatin on its activity and performed different experiments to lower and raise the level of RKIP in cells. Mc Henry performed most of the cell migration assays. Additional chemical analysis was performed by William Lane of the Harvard Microchemistry and Proteomics Analysis Facility.

Funding for the research was provided by the National Cancer Institute of the National Institutes of Health, and the American Cancer Society.

University of Illinois at Chicago

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