For years, researchers have puzzled over how some cells guide themselves toward a chemical that spreads itself around. Now, in the Feb. 11 issue of Science, Johns Hopkins researchers identify a protein that accumulates toward the front end of a cell and helps it "sense" its way to a target.
"Gradient sensing is important in everything from inflammation, disease fighting and blood vessel growth to wound healing and prenatal development," says Peter Devreotes, a professor of biochemistry and senior author of the study. The finding, he says, brings researchers one step closer to understanding this chemical-sensing mechanism and using it to develop treatments.
"If we understand the process, in the future we may be able to encourage or inhibit it," Devreotes says. "This could be beneficial in encouraging wounds to heal, treating cancers by slowing blood vessel growth or reducing inflammation thereby controlling arthritis."
The process by which cells are able to move themselves toward certain targets is known as chemotaxis. When a cell wants to attract another cell, it releases signaling molecules called chemoattractants. These molecules travel toward the other cell and set up a shallow pool around it. The cell then will move toward the source, even when the number of chemoattractant molecules near the front of the receptive cell is only 10 percent higher than near the back. In addition, one edge of the cell, known as the "leading" edge, is more sensitive to stimulation, which further helps guide the cell toward its target. Given these pieces of information, pondered researchers, how did the cell know which direction to travel, and how did it determine its leading edge?
To answer the questions, Devreotes and his colleagues have been studying an amoeba named Dictyostelium, which behaves like many chemotactic cells. This "social amoeba" responds to a chemoattractant known as cAMP, and its response allows it to commune with its fellow amoebae in survival maneuvers. Research in the last decade on Dictyostelium demonstrated that cells use receptors coupled to G-proteins to sense chemoattractants. Just like other chemotactic cells, the amoebae can sense shallow gradients and have only one leading edge.
Devreotes and his colleagues searched for unevenly distributed proteins within the social amoebae that could explain how cells sense direction. They knew that when chemoattractant molecules dock on receptors, the receptors change their shape, and this change attracts G proteins floating in the cell's membranes. When researchers examined the distribution of receptors, however, they found that the receptors were distributed equally around the cell.
In 1998, Devreotes and his colleagues hit the lottery when, after sorting through a number of chemicals inside cells, they discovered that the leading edge of a cell contains greater amounts of specific proteins. These proteins, called PH domain-containing proteins, float freely in the body of the cell but are pulled to one side when the G-protein signals are activated. The researchers did this by attaching fluorescent green protein tags to PH domain proteins and then peering through a microscope to determine to which side of the cell these tagged proteins flocked after being subject to cAMP. They discovered that the fluorescent proteins reliably marked the places on the membrane where the G-protein signals are active.
In Science, the researchers say they now know what makes the cell's leading edge more sensitive to stimulation. They attached the fluorescent green protein to a part of the G-protein. When they examined the cells under the microscope, they found the G-proteins were accumulated on the cell membrane toward the leading edge. In another experiment, the Hopkins researchers chemically paralyzed the cells and caused them to lose their leading edge. The researchers found that the G-proteins then became evenly distributed around the outside of the cell and that the cells became equally sensitive at all points.
"What this tells us is that a cell can sense all over its surface, but it can only lead with its front end," Devreotes says. The researchers say that although others have suggested that an uneven distribution of proteins might be involved in chemotaxis, theirs is the first such protein to be concretely identified as doing so.
More information on chemotaxis research can be found on the Devreotes website, http://www.med.jhu.edu/devreotes.
Other authors of the study are Tian Jin, Ning Zhang, Yu Long and Carole Parent. The National Institutes of Health funded the research.