How cells size up their growth opportunities

CAMBRIDGE, Mass. – The intricate mechanisms that switch cell growth on and off are regulated by mammalian target of rapamycin (mTOR) protein complexes, which sense nutrients within the cell.  When amino-acids are abundant, the protein complexes promote cellular growth, and when nutrients are scarce they signal that hard times are ahead to the cell.  But just how nutrients regulate mTOR signaling to control size has remained a mystery.  Now, scientists in the lab of Whitehead Member David Sabatini have found the first step in the process.

 “What connected amino acids to mTOR was a black box,” says Sabatini, who is also an associate professor of biology at Massachusetts Institute of Technology. “We have found a new mechanism for regulating mTOR that brings us one step closer to understanding how mTOR senses nutrient availability and how deregulation of this pathway may be implicated in diseases such as cancer and diabetes.” 

Several years ago, Sabatini’s lab discovered that mTOR, a major player in cell growth, exists in two distinct protein complexes, mTORC1 and mTORC2.  Both complexes are at the center of many disease-related signaling pathways.  mTORC1 regulates cell growth while mTORC2 regulates cell division and survival. 

Now, by focusing on mTORC1 in human cells, the scientists have found that a family of small guanosine triphosphatases (GTPases) known as Rag proteins control where the protein complex sits in the cell and how it responds to amino acids.

The findings, published by Science Express on May 22, reveal that once the Rag proteins sense amino acids, they promote the shuttling of mTORC1 from the cell’s periphery to a cellular compartment near the nucleus called the late endosome. “That’s where we believe that the protein complex binds to an activator protein called Rheb, signaling the cell to grow,” says Yasemin Sancak, first author of the paper and a graduate student in the Sabatini lab.

Looking at the expression of Rag proteins in different human tissues and disease models may lead to identifying potential targets for drug therapies.

“This new pathway enables us to better understand growth regulation, but we also might expect that aberrant control of this pathway could have implications in diseases,” explains Sabatini. “For example, mTOR is a key intracellular part of a number of signaling pathways that can be abnormally activated in cancer.  It could be that this new pathway may also be mutated in cancer.”

Understanding this pathway may also lead to insights about type 2 diabetes since increased mTOR activation has been linked to insulin insensitivity over time.  

“Amino acid levels are an important mediator of insulin resistance and the mTOR pathway plays a role in this mediation,” says Sancak. “Now that we’ve discovered the proteins that connect nutrients to the mTOR pathway, we can better decipher how over-eating or an abundance of nutrients causes these genes to over-activate the mTOR pathway, therefore contributing to insulin resistance.”

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David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

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Sancak, S. et al. "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1." Science Express, on-line publication May 22, 2008