Study reveals key molecular link in major cell growth pathway

October 19, 2017, Whitehead Institute for Biomedical Research

A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which involves a critical cellular growth pathway known as mTOR, sheds light on a key aspect of cells' metabolism that involves tiny cellular compartments, called lysosomes, and harnesses a sophisticated technology for probing their biochemical content. The researchers' findings also implicate a new protein, SLC38A9, as a potential drug target in pancreatic cancer. Their study appears in the October 19th issue of the journal Cell.

"SLC38A9 is a really elegant protein that ties together two critical functions: activating a key pathway that controls cell growth and releasing the substrates, namely amino acids, needed for that growth," says senior author David Sabatini, a Member of Whitehead Institute, a professor of biology at Massachusetts Institute of Technology, and investigator with the Howard Hughes Medical Institute. "This was a totally unexpected finding, one that has important implications for human diseases, including pancreatic cancer."

Amino acids are one of the basic building blocks of life. When strung together in different combinations, they make a stunning array of proteins that carry out a variety of biological functions. Amino acids typically accumulate in two locations within : either freely floating within the cellular milieu or sequestered inside the lysosomes. For the last decade, Sabatini and his laboratory have studied the mechanisms by which cells sense the levels of amino acids at these sites and translate that information into subsequent go/no-go decisions about growth.

About three years ago, Sabatini and his colleagues, as well as other scientists, discovered SLC38A9, a protein embedded within the outer surface of lysosomes. Although its function was not entirely clear at the time, the researchers suspected it worked as a kind of sensor by reading out the levels of amino acids within lysosomes (specifically the amino acid arginine) and then activating downstream signals for growth.

To clarify how SLC38A9 works, the researchers, including the study's first authors Gregory Wyant and Monther Abu-Remaileh, eliminated or "knocked out" its function in cells. Since they hypothesized that it worked passively as an amino detector, they did not expect to see major changes in the levels of amino acids inside the lysosomes. But that is precisely what they found—especially for the so-called essential amino acids, which cannot be synthesized by the human body and therefore must be acquired from food. When SLC38A9 function was absent, the levels of these essential amino acids in lysosomes went up. And when Wyant and his colleagues boosted the protein's function to higher than normal levels, they observed the opposite effect.

"These were some big clues that SLC38A9 was doing more than we imagined, and they suggested that SLC38A9 could transport amino acids out of the lysosome," says Wyant, a graduate student in Sabatini's laboratory. The researchers confirmed this suspicions in follow-up experiments, which revealed that SLC38A9 is necessary for these , such as leucine, exit from lysosomes.

The amino acids needed to fuel cell growth are often recycled from intact proteins. That includes proteins found inside cells (through a process called autophagy), as well as those found outside (known as macropinocytosis). Both of these recycling streams converge on the lysosome, and, as Sabatini's team discovered, depend on SLC38A9 activity.

Pancreatic cancer cells are known to be highly dependent on the flow of from the . When the researchers knocked out SLC38A9 function in these cells, either in human cell lines or mouse models, tumor growth was significantly reduced. In contrast, normal cells appeared to be unaffected.

"Our results suggest that an inhibitor of SLC38A9 may provide a way to specifically target cells," says Sabatini.

Yet before such therapeutic possibilities can be explored, additional research on SLC38A9 is needed, including three-dimensional studies of the protein as well as a deeper understanding of its regulation. These will help the researchers develop a more complete picture of its molecular abilities—an important stepping-stone toward developing drugs that can disable it.

A key capability that underlies the new Cell study is the technical wherewithal to peer into lysosomes and analyze their biochemical makeup. These structures make up only a tiny fraction of the overall volume of a cell—just 2 percent—and their content is highly dynamic. Abu-Remaileh and Wyant pioneered a strategy for rapidly isolating lysosomes and detecting the metabolites within them.

"We would not have discovered the majority of these findings without this method," said Abu-Remaileh, a postdoctoral fellow in Sabatini's laboratory. "It is allowing us to address some really important and longstanding questions about the biology of lysosomes."

Explore further: Scientists identify first nutrient sensor in key growth-regulating metabolic pathway

More information: Wyant G, Abu-Remaileh M, et al. "mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient." Cell DOI: 10.1016/j.cell.2017.09.046

Related Stories

Scientists identify first nutrient sensor in key growth-regulating metabolic pathway

January 7, 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.

Scientists identify sensor that modulates key metabolic pathway

March 11, 2016
Only recently have scientists begun to tease apart the molecular links between specific nutrients and mTORC1, a cellular signaling pathway that controls growth and metabolism. Now Whitehead Institute researchers have elucidated ...

Starving pancreatic cancer cells: Scientists identify potential pancreatic cancer target

October 17, 2016
Researchers have found that a protein called SLC6A14 is overexpressed by several fold in pancreatic tumors taken from patients and in cancerous pancreatic cells lines compared with normal pancreatic tissue or normal pancreatic ...

Amino acids in diet could be key to starving cancer

April 19, 2017
Cutting out certain amino acids—the building blocks of proteins—from the diet of mice slows tumour growth and prolongs survival, according to new research published in Nature.

Recommended for you

Forces from fluid in the developing lung play an essential role in organ development

January 23, 2018
It is a marvel of nature: during gestation, multiple tissue types cooperate in building the elegantly functional structures of organs, from the brain's folds to the heart's multiple chambers. A recent study by Princeton researchers ...

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

0 comments

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.