Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists Identify First Nutrient Sensor in Key Growth-Regulating Metabolic Pathway

08.01.2015

Known as much for its complexity as its vital role in regulating cellular and organismal growth, the mechanistic target of rapamycin complex 1 (mTORC1) pathway has seemingly been acting in mysterious ways.

Through a variety of mechanistic interactions, mTORC1 interprets cues in the cellular environment, including the availability of nutrients, and signals the organism to act accordingly. mTORC1 is apt to trigger growth during times of abundance and dial back metabolism when food is scarce.

Owing to years of intense scrutiny in the lab of Whitehead Institute Member David Sabatini, the key players of this pathway—whose deregulation is associated with diseases ranging from diabetes to cancer to epilepsy—have gradually been brought to light. Yet, one essential question remained unanswered: How exactly does mTORC1 actually detect the presence of nutrients?

Now, it seems, scientists in Sabatini’s lab have at least a partial answer, describing for the first time a protein that appears to sense the amino acid arginine. The discovery of this transmembrane protein, known as SLC38A9, is reported this week in the journal Science.

“No one doubts that this is an important pathway, with implications for aging, cancer, and diabetes, and we had figured out the core machinery of the pathway,” says Sabatini. “But the mystery has been what are the sensors? Now we’ve found what is likely the first nutrient sensor. This is what connects that core machinery to the world around it.”

The finding suggests a model in which mTORC1, located at the surface of cellular components known as lysosomes, receives “go/no-go” signals from a family of enzymes dubbed Rag GTPases. It had been known that the Rags convey information about nutritional status to mTORC1, but it wasn’t clear how the Rags came by this information. Through a series of experiments, researchers found that SLC38A9 is capable of transporting and directly interacting with amino acids, the building blocks of proteins.

Further, they found that in cells overexpressing SLC38A9, mTORC1 signaling is activated even in the absence of amino acids. On the flipside, they found mTORC1 activation defective in cells engineered to lack expression of SLC38A9. Taken together, such compelling evidence points to SLC38A9 as an amino acid sensor, tipping off the Rags to the availability of nutrients.

“It’s like a relay race and this protein is what starts the race,” says Zhi-Yang Tsun, a graduate student in Sabatini’s lab and co-first author of the Science paper. “We’ve been looking for a long time for a molecule like this. It has all the properties consistent with a sensor.”

As new components of the pathway are identified and their roles elucidated, the number of potential targets that could be manipulated therapeutically increases. Historically, drug development activities in this space have focused on blocking mTORC1 activation, in part because hyperactivation of the pathway can lead to aberrant growth seen in cancer or metabolic abnormalities associated with diabetes. Intriguingly, because SLC38A9 activates the pathway, it may represent a target for clinical situations in which growth stimulation is desirable.

“It would be interesting to have to have small molecular handles to perturb the pathway, turning it on or off,” says Shuyu Wang, another Sabatini lab graduate student and co-first author of the Science paper. “In this case, one could think about situations where you would want to increase protein synthesis, perhaps to treat muscle atrophy and disease-related weight loss.”

Although the discovery of the first nutrient sensor in this pathway represents an important advance, the researchers know much work lies ahead. SLC38A9’s specificity for arginine suggests that many more such sensors—for other amino acids and glucose, for example—interact either directly or indirectly with mTORC1. Identifying them will thus remain a focus of the lab for years to come.

This work was supported by the National Institutes of Health (grants R01 CA103866 and AI47389), the United States Department of Defense (grant W81XWH-07-0448), the Howard Hughes Medical Institute, a National Defense Science and Engineering Fellowship, a National Science Foundation Graduate Research Fellowship, an American Cancer Society - Ellison Foundation Postdoctoral Fellowship, and a German Academic Exchange Service/DAAD Fellowship.

Written by Matt Fearer

* * *

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 Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

* * *

Full Citation:

“Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1”

Science, January 7, 2015

Shuyu Wang (1,2,3,4), Zhi-Yang Tsun (1,2,3,4), Rachel Wolfson (1,2,3,4), Kuang Shen (1,2,3,4), Gregory A. Wyant (1,2,3,4), Molly E. Plovanich (6), Elizabeth D. Yuan (1,2,3,4), Tony D. Jones (1,2,3,4), Lynne Chantranupong (1,2,3,4), William Comb (1,2,3,4), Tim Wang (1,2,3,4), Liron Bar-Peled (1,2,3,4)*, Roberto Zoncu (1,2,3,4)**, Christoph Straub (5), Choah Kim (1,2,3,4), Jiwon Park (1,2,3,4), Bernardo L. Sabatini (5), and David M. Sabatini (1,2,3,4)

1. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.

2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

3. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

4. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.

5. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.

6. Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.

* Present address: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA

** Present address: Department of Molecular and Cell Biology, University of California
Berkeley, Berkeley, CA 94720, USA

Matt Fearer | newswise
Further information:
http://www.wi.mit.edu

Further reports about: Biomedical Cambridge Harvard Sabatini Technology amino amino acid mTORC1 pathway

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>