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Gene responsible for hereditary cancer syndrome found to disrupt critical growth-regulating pathway
Date:11/4/2013

CAMBRIDGE, Mass. (November 4, 2013) Whitehead Institute scientists report that the gene mutated in the rare hereditary disorder known as Birt-Hogg-Dub cancer syndrome also prevents activation of mTORC1, a critical nutrient-sensing and growth-regulating cellular pathway.

This is an unexpected finding, as some cancers keep this pathway turned on to fuel their unchecked growth and expansion. In the case of Birt-Hogg-Dub syndrome, the mutated gene prevents mTORC1 pathway activation early in the formation of tumors. Reconciling these opposing roles may give scientists a new perspective on how cancer cells can distort normal cellular functions to maintain their own harmful ways.

Cells use the mTORC1 (for "mechanistic target of rapamycin complex 1") pathway to regulate growth in response to the availability of certain nutrients, including amino acids. Whitehead Member David Sabatini and other researchers have teased apart many components of this pathway, but the precise mechanism by which nutrient levels are actually sensed has remained elusive. Recently, Sabatini and his lab determined that a family of proteins known as Rag GTPases act as a switch for the pathwaywhen nutrients are present, the Rag proteins turn on the mTORC1 pathway.

Now, several members of the Sabatini lab, including graduate student Zhi-Yang Tsun, have determined that the FLCN protein acts as a trigger to activate the Rag protein switch. Their work is described in the November 7 issue of the journal Molecular Cell.

"Zhi has ascribed a molecular function to this protein, and that's a major contribution," says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. "For the first time, we have a biochemical function that's associated with it. And in my view, that's an important first step to understanding how it might be involved in cancer."

Before Tsun's work, very little was known about FLCN's r
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Contact: Nicole Rura
rura@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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