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The protein key to regulating cell growth

Findings point to new therapeutic target in pancreatic cancer...


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. "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 cells: 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, researchers eliminated or "knocked out" its function in cells. Thought to work passively as an amino acid detector, they did not expect to see major changes in levels of amino acids inside 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, levels of essential amino acids in lysosomes went up. But when Gregory Wyant, graduate student, Sabatini laboratory, and lab colleagues boosted SLC38A9 protein function to higher than normal levels, they observed levels of essential amino acids in lysosomes go down.

"These were some big clues that SLC38A9 was doing more than we imagined, and suggested that SLC38A9 could transport amino acids out of the lysosome," explains Wyant. The researchers confirmed this suspicions in follow-up experiments, which revealed that SLC38A9 is needed by essential amino acids, such as leucine, to 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 amino acids from the lysosome. When researchers knocked out SLC38A9 function in either 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 pancreatic cancer 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."

Abstract Highlights
SLC38A9 is a lysosomal arginine sensor for the mTORC1 pathway
SLC38A9 transports several essential amino acids in an arginine-regulated fashion
Leucine produced via lysosomal proteolysis requires SLC38A9 to activate mTORC1
SLC38A9 is required for macropinocytosed protein to support pancreatic tumor growth

Summary
The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.

Authors: Gregory A. Wyant, Monther Abu-Remaileh, Rachel L. Wolfson, Walter W. Chen, Elizaveta Freinkman, Laura V. Danai, Matthew G. Vander Heiden, David M. Sabatini

Keywords: amino acid sensing, nutrient sensing, mTOR, lysosome, micropinocytosis, autophagy

This work was supported by the National Institutes of Health (NIH, R01 CA103866, R01 CA129105, R37 AI47389, T32 GM007753, F30 CA189333, and F32CA210421), the Department of Defense (W81XWH-15-1-0230, W81XWH-15-1-0337), the European Molecular Biology Organization (EMBO), the Lustgarten Foundation, Stand Up To Cancer (SU2C), the National Cancer Institute (NCI, R01 CA168653, P30CA1405141), and Howard Hughes Medical Institute. 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.

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Illustration from Whitehead Institute.


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