Credit: Jes Andersen/
University of Copenhagen
Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.
The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.
What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.
“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.
“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”
Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.
Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.
Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.
“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.
Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.
The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.
He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.
“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”
All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.
“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”
