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 Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>