Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy

By P. Nicklin, Phil Bergman, Bailin Zhang, E. Triantafellow, Henry Wang, B. Nyfeler, Haidi Yang, M. Hild, C. Kung, Christopher J. Wilson and 7 more. Cell, 2009

1,782 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Biochemistry, Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ed78fa6b817bc78effd0f041cd274f47ce802760

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

In Clinical Biochemistry

In Molecular Biology

Citations in the corpus

Glutamine and cancer: cell biology, physiology, and clinical opportunities. (2013, background): “mTOR, a major positive regulator of cell growth (28).”
Mitochondria and Cancer (2016, background): “Glutamine also plays important roles in transport, where glutamine concentration gradients drive the uptake of essential amino acids, and in signaling, where it activates mTOR (Nicklin et al., 2009).”
Molecular definitions of autophagy and related processes (2017, neutral): “Interestingly, some plants exhibit a microautophagic variant of ribophagy (Niki et al , 2014).”
mTOR signaling at a glance (2009, background): “It was recently shown that leucine, an essential amino acid required for mTORC1 activation, is transported into cells in a glutamine-dependent fashion (Nicklin et al., 2009).”
Regulation of mTORC1 by amino acids (2014, neutral): “Extracellular amino acids must cross the plasma membrane to reactivate mTORC1 after their depletion from cell culture media (31).”
With TOR less is more: a key role for the conserved nutrient sensing TOR pathway in aging (2010, neutral): “Essential amino acids like L-tryptophan, L-phenylalanine, L-arginine, and especially L-leucine activate TORC1 after being transported into the cell in an L-glutamine-dependent manner (Nicklin et al., 2009).”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, neutral): “Other fluorophores such as mCherry are also suitable instead of mRFP,(229) and an imagerecognition algorithm has been developed to quantify flux of the reporter to acidified compartments.(242,267) One of the major advantages of the tandem mRFP/mCherry-GFP reporter method is that it enables simultane”
Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer (2009, background): “A recent study revealed the necessity of glutamine for the well-known stimulatory effect of essential amino acids on the mammalian target of rapamycin (mTOR) pathway (Nicklin et al., 2009).”
Autophagy in the Cellular Energetic Balance (2011, neutral): “The exact mechanismbywhichamino acids signal throughmTOR todownregulate macroautophagy is still unclear, but the contribution of vps34, Ras-related small GTPases (that relocatemTOR to the lysosomal compartment), and a bidirectional transporter that exchanges L-glutamine by essential amino acids have”
The SLC3 and SLC7 families of amino acid transporters. (2013, background): “Interestingly, the coordinated action of ASCT2 and 4F2hc/LAT1 (system L uses system ASC substrates in the cytosol to drive the influx of essential amino acids) regulates mTOR signaling (Nicklin et al., 2009).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “For example, the transport of the leucine that is important for activating mTORC1 requires the efﬂux of glutamine via the bidirectional transporter SLC7A5 (Nicklin et al., 2009).”
Glutaminolysis activates Rag-mTORC1 signaling. (2012, background): “Furthermore, glutamine flux facilitates the uptake of leucine, which in turn regulates mTORC1 and autophagy (Cohen and Hall, 2009; Nicklin et al., 2009).”
Regulation Mechanisms and Signaling Pathways of Autophagy (2009, background): “Extracellular amino acids enter mammalian cells through transporters such as SLC1A5 (solute carrier family 1 member 5) and SLC7A5 (101), and it is proposed that mTORC1 directly senses and is phosphorylated in response to nutrient signals (84); however, recent observations in Drosophila and mammals s”