Researchers Find New Piece of Cell Growth Puzzle

Illustration showing the many factors impacting the protein complex (Raptor, mTOR and GßL) that orchestrates cell growth.

This illustration shows the many factors impacting the protein complex (Raptor, mTOR and GßL) that orchestrates cell growth.

Image: David Guertin

April 29, 2003

Tags: Sabatini LabProtein Function

CAMBRIDGE, Mass. — In biology, size matters. Cell growth, the process whereby cells increase in mass, is critical to many life functions and has been implicated in diseases such as cancer and diabetes. Spurred by the discovery of a cellular pathway that helps switch cell growth on and off, new research links growth to a cell’s ability to sense nutrients in its environment.

This growth-triggering system, known as the mTOR pathway, is composed of a complex of proteins that respond to nutrient cues. To fill in the pieces of this protein puzzle, researchers are working to identify mTOR’s component parts and study how it works.

Scientists at Whitehead Institute for Biomedical Research have discovered a protein that helps regulate the mTOR pathway. This protein, called GßL acts as a bridge stabilizing the interactions between two other proteins central to mTOR function. When GßL is absent or disabled, cells become insensitive to nutrient levels and grow abnormally, a possible cause of disease, say researchers.

The finding, published in this month’s issue of Molecular Cell, brings researchers a step closer to understanding how nutrients regulate cell growth and what happens when this system breaks down.

“As we learn more about mTOR at the cellular level, we can begin to understand its function in the regulation of growth throughout the body,” said David Sabatini, a researcher at Whitehead and leader of the team that published the study. “This complex has opened up a window onto how nutrient signaling is involved in different mammalian processes and provided a new way to investigate the role nutrients and metabolism play in disease.”

The mTOR story began with the serendipitous discovery of rapamycin, a powerful immunosuppresant culled from a random soil sample in the 1970s. Made by bacteria, rapamycin was first used to prevent organ rejection in kidney transplant patients. Although researchers knew that rapamycin was effective and caused fewer side effects than existing treatments, no one understood exactly how or why it worked.

Using rapamycin as a research tool, Sabatini, then a graduate student at Johns Hopkins Medical School, worked backward—exposing cells to the drug and monitoring its effect. Sabatini discovered that rapamycin blocked the activity of a protein called mTOR (mammalian Target of Rapamycin).

“Rapamycin appears to stop cell growth by flipping a pre-existing switch that cells use to sense nutrients in their environment—the cells are tricked into thinking they’re starving,” explained Sabatini. Faced with this faux famine, T cells—the cells responsible for organ rejection—stop growing and dividing in the body, staving off rejection.

Further studies suggested that this was just the tip of the iceberg and that rapamycin was inhibiting a larger, nutrient-sensitive pathway helping to control cell growth regulation. This suspicion was confirmed in 2002 when Sabatini’s lab identified another protein in the mTOR complex. Raptor (regulatory associated protein of mTOR) was found to work in conjunction with the mTOR protein to directly regulate cell size in response to nutrient levels.

In their newest findings, Sabatini and his colleagues have discovered a third protein, GßL, which stabilizes interactions between raptor and the mTOR protein. The balance between GßL and raptor might be perturbed in human disease, said Sabatini, and could be a potential target for therapy.

As the puzzle becomes more complete, researchers said, it’s clear that the process of cell growth has implications beyond those previously thought. “In some cases, a cell becomes insensitive to nutrient signaling and growth goes out of control. This suggests that the appreciation of the role of nutrients and signaling has been underestimated in the study of cancer,” noted Sabatini.

This seems to be the case in tumors caused by tuberous sclerosis, a genetic disease that causes tuber-like growths throughout the body that calcify with age and become hard. In the cells of these tumors, the TOR pathway is insensitive to nutrient starvation. As a result, cell growth goes unchecked and cells become very large. Rapamycin, the drug that inhibits the TOR pathway, may be used to treat the disorder.

The Sabatini lab currently is screening large numbers of cells from various cancer types to find others that that may have dysfunctional TOR pathway regulation and subsequently respond to rapamycin therapy.

by Melissa L. Withers

Full citation:
© Molecular Cell, Vol 11, issue 4, April 2003
“ GßL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR”

Authors: Do-Hyung Kim (Whitehead Institute for Biomedical Research and MIT), Dos D. Sarbassov (Whitehead Institute for Biomedical Research and MIT), Siraj M. Ali (Whitehead Institute for Biomedical Research and MIT), Robert R. Latek (Whitehead Institute for Biomedical Research), Kalyani V.P. Guntur (Whitehead Institute for Biomedical Research and MIT), Hediye Erdjument-Bromage (Memorial Sloan-Kettering Cancer Center), Paul Tempst (Memorial Sloan-Kettering Cancer Center), and David M. Sabatini (Whitehead Institute for Biomedical Research and MIT).

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