Scientists discover new component of key growth-regulating signaling pathway

Jun 14, 2011

(PhysOrg.com) -- Researchers in the lab of Whitehead Institute Member David Sabatini have identified a new substrate of the mammalian target of rapamycin (mTOR) kinase, called Grb10, by using a two-pronged approach of mass spectrometry and kinase specificity profiling.

“These results show that mTOR participates in most key cellular processes, consisting with its established role in common diseases like diabetes, cancer, and neurodegeneration” says Sabatini, who is also a Howard Hughes Medical Institute (HHMI) investigator and a professor of biology at MIT.

The research is published in the June 10 issue of Science.

The Grb10 protein was known to interact with insulin receptors and to inhibit the ability of cells to respond to insulin. By identifying the relationship between Grb10 and mTOR, Peggy Hsu, a former graduate student in the Sabatini lab and first author of the Science paper, was able to show that Grb10 is important for mTOR to inhibit signaling downstream of extracellular growth factors like insulin. This provides researchers with a more detailed understanding of the function of mTOR, especially in the context of cancer, and opens up new areas for mTOR research.

“These results show that mTOR participates in most key cellular processes, consisting with its established role in common diseases like diabetes, cancer, and neurodegeneration” says Whitehead Member David Sabatini.

The role of mTOR in nutrient sensing and regulation of cell growth has been conserved from yeast to worms, flies, and mice.  In humans, it is also important in overall organismal nutrient metabolism and organism size; dysregulation of mTOR has been linked to diabetes and some cancers. Despite its biological and medical importance—drugs that inhibit mTOR are used to treat certain cancers and to suppress the immune system to prevent transplant rejections—little is actually known about the substrates that mTOR targets or the precise manner in which it affects multiple cellular processes.

Hsu, who is now finishing her medical degree at Harvard Medical School, says that until recently, the search for mTOR substrates has been non-systematic and hamstrung by rapamycin’s limited inhibition of mTOR. With the advent of new mTOR inhibitors that target mTOR directly, including the inhibitor Torin1 that Hsu used in her work, researchers are now able to get a more complete picture of what mTOR regulates.

According to Hsu, use of these new mTOR inhibitors in conjuction with and the specificity profiling method will transform both future and current mTOR research.

“I think this will open up different areas of potential exploration,” says Hsu, who worked closely with the labs of Michael Yaffe at MIT and Jarrod Marto at Harvard Medical School. “I hope this work allows other reseachers to make a connection very quickly by looking through our data, and to basically say, ‘Aha! I thought mTOR would be involved in process X. And now maybe I have a way to study it.’ ”

Explore further: Cells build 'cupboards' to store metals

More information: “The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling” Science, June 10, 2011

Related Stories

Impaired activity of the protein MTOR a strain on the heart

Jul 19, 2010

A team of researchers, led by Gianluigi Condorelli, at the University of California San Diego, La Jolla, has generated data in mice that suggest that drugs that inhibit the protein MTOR, which are used to treat several forms ...

Unraveling how cells respond to low oxygen

Aug 05, 2009

Gary Chiang, Ph.D., and colleagues at Burnham Institute for Medical Research (Burnham) have elucidated how the stability of the REDD1 protein is regulated. The REDD1 protein is a critical inhibitor of the mTOR signaling pathway, ...

Drug discovery short-circuits cancer growth

Feb 10, 2009

A new drug that blocks cancer's main source of growth has been created in the lab and proven effective in mice, scientists are reporting. It is now being readied for clinical trials in patients.

Recommended for you

Cells build 'cupboards' to store metals

Dec 17, 2014

Lawrence Livermore researchers in conjunction with collaborators at University of California (link is external), Los Angeles have found that some cells build intracellular compartments that allow the cell ...

Stunning zinc fireworks when egg meets sperm

Dec 15, 2014

Sparks literally fly when a sperm and an egg hit it off. The fertilized mammalian egg releases from its surface billions of zinc atoms in "zinc sparks," one wave after another, a Northwestern University-led ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.