Direct Actions Found for Very Important Protein

A well-known protein, mTOR, is necessary and sufficient to turn on major metabolic pathways in the cell.

The protein mTOR, short for mammalian target of rapamycin, has intrigued scientists for decades because of its role in cellular signaling and cell growth regulation. New research focuses on the direct actions of this molecular VIP and shows the steps it takes to wield its extraordinary power in the cell. The misregulation of mTOR is associated with a variety of different diseases, including diabetes, autism and more than half of the most common human cancers.

Scientists at HSPH, working with others at the Broad Institute and Novartis, report in the July 30 Molecular Cell that mTOR controls fundamental metabolic processes in the cell through regulating just two gene transcription factors.

The authors of the study, including Brendan Manning, an HSPH associate professor of genetics and complex diseases, took two parallel approaches, searching for both genes and molecules involved in cell metabolism that are regulated by mTOR. “We focused on what mTOR itself does since it’s an important enzyme, and there’s very little known about what the actual downstream consequences of its activation are,” said Manning.

mTOR senses cellular growth signals, like nutrients and growth factors, and is involved in the machinery of cellular signaling. Manning and his colleagues found that the protein alone was sufficient to turn on metabolic pathways, such as the breakdown of glucose and fatty acid biosynthesis. Looking more closely, they saw that it exercised its control over these pathways through the regulation of SREBP and HIF1-alpha, proteins instrumental in activating gene transcription.

A metabolic hallmark of cancer cells that distinguishes them from normal tissues is an elevated rate of glycolysis and fatty acid biosynthesis. “What our study demonstrates is that mTOR itself is sufficient to drive those metabolic changes,” said Manning.

For more information, students may contact Brendan Manning at bmanning@hsph.harvard.edu.

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: The National Institutes of Health and the Tuberous Sclerosis Alliance; the authors are solely responsible for the content of this work.