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Johns Hopkins Medicine scientists say a key to cell movement is regulating the electrical charge on the inside of the cell membrane, potentially opening the way to understanding cancer, immune cells and other types of cell movement.
Her experiments on immune cells and amoebas show that a plethora of negative charges lining the membrane’s inner surface can activate pathways of lipids, enzymes and other proteins responsible for nudging a cell in a certain direction.
The results, described in the October issue of nature cell biologyadvance biologists’ understanding of cell movement and may help explain biological processes associated with movement, e.g. B. how cancer cells move and spread beyond the original site of a tumor and how immune cells migrate to areas of infection or wound healing.
“Our cells move around more in our body than we can imagine,” says Peter Devreotes, Ph.D., professor of Isaac Morris and Lucille Elizabeth Hay and Distinguished Service Professor in the Department of Cell Biology at Johns Hopkins University School of Medicine. “Cells move to perform many functions, including as they take in nutrients or divide.”
Many of the molecules involved in cell movement are activated at the cell’s leading edge, or where it forms a kind of foot or protrusion that orients the cell in a certain direction.
Tatsat Banerjee, a graduate student in the Departments of Cell Biology and Chemical and Biomolecular Engineering at Johns Hopkins University and the study’s lead author, began to notice that negatively charged lipid molecules lining the inner layer of cell membranes are not uniform, as scientists previously thought had . He noticed that this group of molecules is constantly leaving the regions where a cell protrudes. Banerjee surmised that a general biophysical property such as electrical charge, rather than a specific molecule, might stimulate and organize the activities of enzymes and other proteins related to cell movement.
To test this idea, Banerjee and Devreotes used a biosensor, a fluorescently labeled, positively charged peptide, to probe the inner lining of the membrane of human immune cells, called macrophages, which engulf invading cells and a single-celled soil dwelling called an amoeba Dictyostelium discoideum.
They found that there was a corresponding reduction in negative electrical charge along the inner membrane when and where the cells formed protrusions. Alternatively, electric charge increased along the resting membrane surface of the cells, helping to recruit more positively charged proteins.
The Johns Hopkins researchers also constructed novel highly charged, genetically encoded molecules that can be moved within the cell by light. Wherever the scientists irradiated the cell with light, new protrusions formed or suppressed them to move the cell in a specific direction, depending on whether the surface charge was reduced or increased.
Devreotes says these experimental results may be the first evidence that the level of generic membrane surface charge plays a causal role in controlling cell signaling and motility.
Working with Pablo Iglesias, Ph.D., and his research team in the Department of Electrical and Computer Engineering at the Johns Hopkins Whiting School of Engineering, the researchers built a computational model to demonstrate how small changes in electrical charges affect the internal membrane impact cell signaling activities.
“The negative surface charge appears to be sufficient and necessary to activate a cascade of biomolecular reactions that have been linked to cell movement,” says Banerjee.
Commenting on the current study in F1000 Faculty Opinions, Martin Schwartz, Ph.D., the Robert W. Berliner Professor of Medicine (Cardiology) and Professor of Biomedical Engineering and Cell Biology at the Yale School of Medicine, who is unrelated to this study , said: “…This paper has the potential to set a new direction in this field.”
Next, the scientists plan to study exactly how and when the electrical charges along the inner membrane are reduced in response to external cues, and exactly how the negative charges are linked to the intricate protein and lipid signaling networks that govern cell movement and others associated processes trigger physiological processes.
The research was funded by the National Institutes of Health (R35 GM118177, S10 OD016374), DARPA and AFOSR MURI.
In addition to Banerjee, Iglesias and Devreotes, Johns Hopkins’ Debojyoti Biswas, Dhiman Sankar Pal and Yuchuan Miao also contributed to the research.
nature cell biology
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