Publication Date:
2015-01-09
Description:
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore, we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384888/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jewell, Jenna L -- Kim, Young Chul -- Russell, Ryan C -- Yu, Fa-Xing -- Park, Hyun Woo -- Plouffe, Steven W -- Tagliabracci, Vincent S -- Guan, Kun-Liang -- K99DK099254/DK/NIDDK NIH HHS/ -- R01 CA108941/CA/NCI NIH HHS/ -- R01CA108941/CA/NCI NIH HHS/ -- R01GM051586/GM/NIGMS NIH HHS/ -- T32 CA121938/CA/NCI NIH HHS/ -- T32CA121938/CA/NCI NIH HHS/ -- T32GM007752/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):194-8. doi: 10.1126/science.1259472. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. ; Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. ; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. kuguan@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567907" target="_blank"〉PubMed〈/a〉
Keywords:
ADP-Ribosylation Factor 1/genetics/metabolism
;
Adaptor Proteins, Signal Transducing/genetics/metabolism
;
Animals
;
Enzyme Activation
;
Gene Knockdown Techniques
;
Glutamine/*metabolism
;
HEK293 Cells
;
Humans
;
Leucine/*metabolism
;
Lysosomes/*enzymology
;
Mice
;
Mice, Knockout
;
Monomeric GTP-Binding Proteins/genetics/*metabolism
;
Multiprotein Complexes/*metabolism
;
Protein Transport
;
TOR Serine-Threonine Kinases/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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