ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells

Fuchs, Bryan C.; Finger, Richard; Onan, Marie C.; Bode, Barrie P.

doi:10.1152/ajpcell.00330.2006

Cited by 119 publications

(116 citation statements)

References 46 publications

(62 reference statements)

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“…in muscle cells [48][49]. Further, such a reduced mTOR signaling might be one reason why Snat3-deficient mice suffer from growth-retardation in the neonatal period…”

Section: Discussionmentioning

confidence: 99%

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan

Busque

Sailer

et al. 2015

Pflugers Arch - Eur J Physiol

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Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney. ABSTRACTGlutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, loss of the Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3 deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and GABA levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion ...

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“…in muscle cells [48][49]. Further, such a reduced mTOR signaling might be one reason why Snat3-deficient mice suffer from growth-retardation in the neonatal period…”

Section: Discussionmentioning

confidence: 99%

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan

Busque

Sailer

et al. 2015

Pflugers Arch - Eur J Physiol

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“…AtCOP10 and AtUEV1B were amplified from Columbia-0 cDNA and HsMUB from SK-HEP cDNA (38) and similarly cloned into pENTR/D-TOPO. The AtCOP10 splice variant At3g13550.1 was gel-excised prior to D-TOPO cloning.…”

Section: Methodsmentioning

confidence: 99%

Arabidopsis Membrane-anchored Ubiquitin-fold (MUB) Proteins Localize a Specific Subset of Ubiquitin-conjugating (E2) Enzymes to the Plasma Membrane

Dowil

Lü

Saracco

et al. 2011

Journal of Biological Chemistry

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The covalent attachment of ubiquitin (Ub) to various intracellular proteins plays important roles in altering the function, localization, processing, and degradation of the modified target. A minimal ubiquitylation pathway uses a three-enzyme cascade (E1, E2, and E3) to activate Ub and select target proteins for modification. Although diverse E3 families provide much of the target specificity, several factors have emerged recently that coordinate the subcellular localization of the ubiquitylation machinery. Here, we show that the family of membrane-anchored ubiquitin-fold (MUB) proteins recruits and docks specific E2s to the plasma membrane. Protein interaction screens with Arabidopsis MUBs revealed that interacting E2s are limited to a well defined subgroup that is phylogenetically related to human UbcH5 and yeast Ubc4/5 families. MUBs appear to interact noncovalently with an E2 surface opposite the active site that forms a covalent linkage with Ub. Bimolecular fluorescence complementation demonstrated that MUBs bind simultaneously to the plasma membrane via a prenyl tail and to the E2 in planta. These findings suggest that MUBs contribute subcellular specificity to ubiquitylation by docking the conjugation machinery to the plasma membrane.

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“…Slc1a5 is up-regulated in multiple types of cancer and has been implicated in mediating net glutamine uptake in cancer cells (Fuchs and Bode 2005). Glutamine uptake into the cell through Slc1a5 has been shown to be essential for regulating mTOR activity (Fuchs et al 2007;Nicklin et al 2009) by making it available for coupling glutamine export to leucine import into the cell through Slc7a5 (Nicklin et al 2009). Slc6a19 preferentially transports neutral amino acids, including leucine, isoleucine, and glutamine.…”

Section: Restoration Of Hexosamine Pathway Flux Enables Growth In Thementioning

confidence: 99%

The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism

Wellen

Lü²,

Mancuso³

et al. 2010

Genes Dev.

325

311

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Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor a (IL-3Ra) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.

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ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells

Cited by 119 publications

References 46 publications

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Arabidopsis Membrane-anchored Ubiquitin-fold (MUB) Proteins Localize a Specific Subset of Ubiquitin-conjugating (E2) Enzymes to the Plasma Membrane

The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism

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