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Q--What did one blood platelet say to the other?
A--Want to stick around awhile?
In fact, a "matchmaker" protein may help pair sticky fibrinogen with hook-like receptors on blood platelets, thereby setting the stage for clots, which can trigger heart attacks, strokes and arterial inflammation, a University of Delaware scientist explains.
Studies of the matchmaker protein--dubbed CIB for its calcium and integrin binding function--may someday suggest new strategies for preventing sudden deaths caused by heart attacks, says Ulhas P. Naik, an assistant professor of biological sciences at UD. The research remains fundamental for now, he cautions, but it should prove useful to drug companies in the future.
"If we can learn exactly what lures these cells together, it might be possible to develop better remedies for blocking platelet aggregation, or clustering," Naik says. "The dating rituals of these cells also may shed light on how cells migrate from place to place, and how white blood cells--the body's police officers--reach the site of an infection."
In 1996, Naik's identification of the CIB protein earned him the American Heart Association's Young Investigator Prize in Thrombosis, awarded every two years to a single researcher whose work is judged best in the world.
Since then, his investigations have focused on yet another player in the courtship of clot-related cells. His latest discovery, nicknamed PAM-1 (for platelet adhesive molecule), seems to prowl the corridors of the bloodstream, arranging dates for various cell pairs.
CIB, on the other hand, is an inside operator, similar to known "regulatory" proteins, which works within platelets to attract the protein fibers that form a framework for blood clots.
When a blood vessel is injured, biochemical catalysts (agonists) such as thrombin send signals into platelets, changing the shape of a receptor or "integrin" protruding from the cell's surface. A sticky, fibrous protein in the bloodstream, fibrinogen takes the hint, latching onto the available integrin (glycoproteinIIb/IIIa), and causing the formation of platelet aggregates, according to Naik, whose work is funded by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH).
Creating the mood for a match
Naik isolated the matchmaker protein from a vast pool of potential protein partners by adding "bait"--specifically, the integrin's tail.
Inside a yeast cell, each solo protein searched for a suitable partner. Naik knew he had a match when the process of gene expression was triggered as a result of a protein-protein interaction.
In this way, Naik can screen a million cloned proteins for naturally forming couples--a widely used technique, which he described in the Journal of Biological Chemistry (Feb. 21, 1997, vol. 272, no. 8, pp. 4651-5654). "When one or two yeast colonies change colors," he explains, "I know that they are interacting." A series of subsequent experiments can then pinpoint the true interaction.
A super cell glue?
Most recently, Naik isolated an adhesive molecule that seems to work like glue, prompting different cells, including platelets, to stick together. Falling within the large family of cellular adhesive molecules (CAMs), PAM-1 seems to travel in pairs.
"Two PAM-1 molecules on two different proteins will interact with each other," Naik says. "This is called a homophilic interaction. I have found blobs of these PAM-1 molecules where two cells are attached."
The glue-like molecules are expressed by heart, endothelial, lung, kidney, pancreas and other cells, according to Naik. They seem to function as receptors on the surface of platelet cells, he adds.
"Clots begin with platelet activation," he notes. "If we could slow or stop that process, we could develop additional tools for combating a wide range of heart diseases."
PAM-1's precise activities remain a mystery, Naik emphasizes, but he plans continued studies, in collaboration with colleagues including Patricia A. DeLeon, a UD professor of human genetics, who has been investigating another adhesive molecule involved in reproduction. DeLeon's goal is to localize the gene that expresses PAM-1 within the human genome and in the mouse, an excellent model organ system.
"Once we find where the gene resides," DeLeon says, "then we can begin to ask whether any disease that might be expected for an alteration of the gene is linked to the same region. Most of these adhesive proteins are multi-functional, so I think we'll find that PAM-1 may play a number of roles. By mapping the gene in both the human and mouse, we will increase our chances of identifying its possible role in diseases."
Studies of integrins and cell adhesive molecules could promote a better understanding of a variety of ailments, from thrombosis and inflammation to heart attacks and cancer, as well as physiological processes such as reproduction. Naik's work "is contributing to our fundamental understanding of how individual cells in complex tissues communicate," says Daniel D. Carson, chairperson of UD's Department of Biological Sciences. "His studies have important implications for embryonic development as well as disease progression."
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