TY - JOUR
T1 - Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids
AU - Averous, Julien
AU - Lambert-Langlais, Sarah
AU - Carraro, Valérie
AU - Gourbeyre, Ophélie
AU - Parry, Laurent
AU - B'Chir, Wafa
AU - Muranishi, Yuki
AU - Jousse, Céline
AU - Bruhat, Alain
AU - Maurin, Anne Catherine
AU - Proud, Christopher G.
AU - Fafournoux, Pierre
N1 - Funding Information:
This work was supported by grants from the Institut National de la Recherche Agronomique (INRA) and from the Fondation ARC pour la Recherche sur le Cancer .
PY - 2014/9
Y1 - 2014/9
N2 - The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR. Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic.
AB - The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR. Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic.
KW - Amino acids
KW - Leucine
KW - Lysosome
KW - MTORC1
KW - Rags
UR - http://www.scopus.com/inward/record.url?scp=84901828078&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2014.04.019
DO - 10.1016/j.cellsig.2014.04.019
M3 - Article
C2 - 24793303
AN - SCOPUS:84901828078
SN - 0898-6568
VL - 26
SP - 1918
EP - 1927
JO - Cellular Signalling
JF - Cellular Signalling
IS - 9
ER -