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Bidirectional transport of amino acids regulates mTOR and autophagy

Nicklin, Paul and Bergman, Phillip and Zhang, Bailin and Triantafellow, Ellen and Wang, Henry and Nyfeler, Beat and Yang, Haidi and Hild, Marc and Kung, Chi-Yun and Wilson, Christopher and Myer, Vic and Mackeigan, Jeff and Porter, Jeffrey and Wang, Y Karen and Cantley, Lewis C and Finan, Peter and Murphy, Leon (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 136 (3). pp. 521-534. ISSN 1097-4172

Abstract

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: SIGNALING; PROTEINS; CELLBIO
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Date Deposited: 22 Feb 2010 11:50
Last Modified: 31 Jan 2013 00:51
URI: https://oak.novartis.com/id/eprint/1669

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