Format

Send to

Choose Destination
Science. 2015 Jan 9;347(6218):188-94. doi: 10.1126/science.1257132. Epub 2015 Jan 7.

Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.

Author information

1
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
2
Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.
3
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
4
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.

PMID:
25567906
PMCID:
PMC4295826
DOI:
10.1126/science.1257132
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center