Embargoed by Science for 2 p.m. EST Thursday, Nov. 29, 2001

UCSD Researchers Identify Protein With Dual Role
In Regulation of Cellular Processes

The unique dual-action role of a natural regulatory protein that controls cellular function has been described by researchers at the University of California, San Diego (UCSD) School of Medicine in a study published in the November 30, 2001 issue of the journal Science.

This is the first scientific evidence that links an important regulatory protein to both cell signaling (a complex cellular communication process) and membrane trafficking (the movement of substances through the cell’s outer membrane to targeted areas within the cell).

Sequentially, the cell signaling process begins with a G protein coupled receptor on the cell's surface. The receptor binds to an external stimulus and transmits the desired effect into the cell's interior, stimulating a G protein. Composed of three subunits - alpha, beta and gamma - the G protein divides into a G alpha subunit and G beta/gamma units, which then activate an effector (E)molecule at the end of the pathway.RGS-PX1 protein is introduced in the process, between the separated G alpha and G beta/gamma subunits, the normal process is reversed.

Bin Zheng, M.S., the study’s first author, and Marilyn Farquhar, Ph.D.

According to senior author Marilyn Farquhar, Ph.D., chair of UCSD’s Department of Cellular and Molecular Medicine, the findings are important to the scientific community because they link previously unconnected areas and offer new avenues of disease research.

“For example,” she added, “these findings offer potential targets for the development of new drugs to help people with heart failure, hormone imbalances and cancer, which are all linked to flaws in cell signaling or trafficking.”

In its cell-signaling role, RGS-PX1 regulates a molecular on-off switch called a G protein alpha (Ga) subunit, which is important for cellular processes that affect a variety of conditions such as normal heart beat, hormone secretion, and kidney function. When RGS-PX1 is present, the Ga subunit activity is turned off.

When molecules such as Epidermal Growth Factor (EGF) are taken up by cell, they are routed through a well-defined pathway.For example, EGF and EGF receptor aretransported through the cell in a network of tubules and vesicles called endosomes,then delivered to a lysosome, which is the terminal compartment - or designated target - of the trafficking pathway. Normally, when it reaches the lysosome, EGF and its receptor are degraded - a process critical for EGF's multiple activities including cell proliferation, differentiation and migration. RGS-PX1 stops this process and slows degradation of EGF and its receptor.

Bin Zheng, M.S., a graduate student in UCSD’s Molecular Pathology Graduate Program and the study’s first author, noted that RGS-PX1 also modulates trafficking within the cell, specifically the movement of cellular components called growth factor receptors, which influence cell and division.

In normal activity, when cell growth is completed, growth factor receptors cease their activity. RGS-PX1 delays the natural degradation of growth factor receptors and, instead, allows cells to continue to proliferate, such as in the growth of cancerous tumors.

“Now we need more studies to determine other molecules involved and how RGS-PX1 is activated in its regulation of cell signaling and growth factor trafficking,” Zheng said.

Farquhar likened it to the electrical circuits in a house where the current comes in one main circuit, then branches out to different rooms.

Dr. Farquhar and  Zheng work in their UCSD lab

“Signaling circuits are like that,” she said. “Right now we’re in the family room, where we discovered the protein. We’re now trying to work our way back to the entry point where this is controlled, to better understand how and why RGS-PX1 gets activated.”

Found in yeast, plants and mammals, there are at least 20 RGS proteins that were first described by researchers about six years ago. The Farquhar team found one of the first RGS proteins and has continued their studies since then. About two years ago, Zheng found the RGS-PX1 protein while searching many of the new protein and DNA sequence databases, then determined its function with studies of various animal cells. The team named the protein RGS-PX1 to include both its roles: RGS for the G protein signaling function, and PX to signify its physical structure related to trafficking.

Additional authors of the study were Gordon Gill, M.D., professor and interim dean for scientific affairs, UCSD School of Medicine; Paul A. Insel, M.D., professor, and Rennolds S. Ostrom, Ph.D., post doctoral fellow, UCSD Department of Pharmacology; Christine Lavoie, Ph.D., assistant project pharmacologist, UCSD Department of Cellular and Molecular Medicine; and Yong-Chao Ma, Ph.D., post doctoral fellow and Xin-Yun Huang, Ph.D., professor, Department of Physiology, Weill Medical College of Cornell University.

The research was funded by the National Institutes of Health.

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