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Scientists Discover How Cells Move a Critical Protein

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Duke Health News 919-660-1306

DURHAM, N.C. -- Nearly every cell in the body has a primary cilium, a crucial antenna-like protrusion that processes signals and cellular responses. Defects in the cilium are linked with a wide variety of illnesses and disorders including cancer, blindness, polycystic kidney disease and others.

Scientists at Duke University Medical Center have found the pathway through which a signaling protein called Smoothened (Smo) can move into the primary cilium, a discovery that could eventually translate into therapeutic treatments for cancer.

"This is the first time that anyone has shown how cell surface receptors like Smo get into the cilium where they must reside to signal properly," said first author Jeffrey Kovacs, Ph.D., a post-doctoral fellow in the Duke Departments of Medicine and Immunology.

Improper Smo signaling is known to result in formation of tumors, yet no treatments directed at Smo activity are currently available. Smo is a member of a large family of cell surface receptors termed G-protein coupled receptors, or GPCRs, first described by co-author Robert J. Lefkowitz and his group. Members of the GPCR family are the targets of about 60 percent of drugs that are on the market to treat clinical conditions, Kovacs said. Figuring out exactly which mechanisms govern Smo signaling could lead to treatments, he said.

In this latest study, the team found that beta arrestin proteins are responsible for moving Smo to the primary cilium.

"The beta arrestin molecules mediate the interaction of the protein Smo with a motor protein that literally grabs the Smo and moves it to the primary cilium," said co-author Robert J. Lefkowitz, M.D., James B. Duke Professor of Medicine and investigator of the Howard Hughes Medical Institute. "We knew that the beta arrestins interacted with Smo, but we didn't fully appreciate the complexity of this interaction until now."

"The next step in our research is to look for ways that other GPCRs are put into position, not just Smoothened," Kovacs said. "We want to know how these receptors signal in a movement-dependent way. This may give us an idea about how different molecules work to turn on or turn off the signaling pathways" that cause these abnormal clinical conditions.

Dr. Lefkowitz theorized and discovered GPCRs years ago. His laboratory later discovered beta arrestins, named for their ability to turn off or "arrest" the receptors' activity. Recently, the lab has been discovering ways in which beta arrestins turn on signaling pathways as well as turning them off.

Other authors of the paper include Erin J. Whalen, Ph.D., Renshui Liu, Ph.D., Jihee Kim, Ph.D., Minyong Chen, Ph.D., Jiangbo Wang, Ph.D., and Wei Chen, Ph.D., of the Duke Department of Medicine, and Kunhong Xiao, Ph.D., of the Duke Department of Biochemistry. This study was funded by two NIH Research Project Grants and an NIH postdoctoral training grant.

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