BOSTON -- Even yeast understand austerity. A finely tuned system evolved early on to help cells survive in a world where good times come as fast as they go. The system, a molecular switch found in organisms from yeast to humans, involves a nutrient-sensing protein that turns growth on in times of plenty and shuts it off when times are lean.
New work from the lab of Wenyi Wei, PhD, an investigator in the Department of Pathology at Beth Israel Deaconess Medical Center and J. Wade Harper, PhD, of the Department of Cell Biology at Harvard Medical School (HMS), has uncovered the mechanism that flips this switch. They found that mTOR, the mammalian version of this key protein, turns itself on in a positive feedback loop involving destruction of DEPTOR, the protein that holds the mTOR switch in the off position.
The results are reported in the Oct. 20 online edition of Molecular Cell along with two other papers reporting similar findings.
The mTOR pathway has been linked to cancer in cases where an abnormality in the signaling allows cells to grow uncontrollably regardless of fitness, so complete understanding of the intricacies of mTOR signaling could contribute to the design of novel cancer treatments. The pathway has also been linked to cardiovascular, autoimmune and metabolic diseases. This new work answers key questions about how the switch flips but also raises intriguing new questions about how an inactivated protein can activate itself.
When Wei, Assistant Professor of Pathology at HMS, began this investigation, parts of the mTOR switch mechanism had already been uncovered. For instance, DEPTOR holds mTOR in the off position by binding with it and blocking its activity. Further, DEPTOR vanishes through ubiquitination, a process that tags proteins for destruction and sends them to the proteasome, a disposal system that shreds proteins when they are no longer needed.
But the molecular mechanism that triggers
|Contact: Bonnie Prescott|
Beth Israel Deaconess Medical Center