SNAT2 transceptor signalling via mTOR: A role in cell growth and proliferation?

Pinilla, Jorge

doi:10.2741/332

Cited by 36 publications

(45 citation statements)

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“…This is supported by the idea of AA transporters functioning as "transceptors" (receptor-transporter) (221), which has been demonstrated for SNAT2 (SLC38A) in breast cancer cells (172). The implications and the extent of the AA sensing by transceptors in milk protein synthesis are currently unknown but may be a phenomenon worth investigating.…”

Section: Aa Transporters and Milk Protein Synthesismentioning

confidence: 55%

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Osorio

Lohakare

Bionaz

2016

Physiological Genomics

182

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Section: Aa Transporters and Milk Protein Synthesismentioning

confidence: 55%

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Osorio

Lohakare

Bionaz

2016

Physiological Genomics

182

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“…Several amino acid transporters of the SLC protein family have been implicated in mTORC1 regulation. For example, SLC1A5 and SLC3A2 control mTORC1 activity specifically upon glutamine transport (38), while inhibition of amino acid transport through SLC38A2 activates mTORC1 (40). However, the plasma membrane localization of SLC1A5, SLC3A2, and SLC38A2 makes them ineligible for sensing amino acids at lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9

Jung

Genau

Behrends

2015

Molecular and Cellular Biology

226

215

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The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Depletion of SLC38A9 inhibits mTORC1 activity in the presence of amino acids and in response to amino acid replenishment following starvation. Conversely, SLC38A9 overexpression causes RHEB (Ras homolog enriched in brain) GTPase-dependent hyperactivation of mTORC1 and partly sustains mTORC1 activity upon amino acid deprivation. Intriguingly, during amino acid starvation mTOR is retained at the lysosome upon SLC38A9 depletion but fails to be activated. Together, the findings of our study reveal SLC38A9 as a Rag-Ragulator complex member transducing amino acid availability to mTORC1 activity. The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism; therefore, its activity often is altered in cancer (1). mTORC1 comprises several subunits, including the serine/threonine kinase mTOR, regulatoryassociated protein of mTOR (RPTOR), mammalian lethal with SEC13 protein 8 (MLST8), AKT1 substrate 1 (AKT1S1), and DEP domain containing mTOR-interacting protein (DEPTOR) (2, 3). The mTORC1 complex serves as a platform to integrate upstream signals, such as the nutritional state, growth factors, and energy level. Some of these signals, for example, insulin stimulation or low energy levels, are converged by phosphorylation of the tuberous sclerosis complex (TSC), as reviewed in reference 4. The TSC is composed of the proteins TSC1, TSC2, and TBC1D7 and acts as a GTPase-activating protein (GAP) for the small GTPase RHEB (Ras homolog enriched in brain), stimulating the transition from its active GTP-bound to its inactive GDP-bound state (5-7). RHEB is anchored to endomembranes, especially to lysosomes, via its prenylated C-terminal CAAX box motif and promotes mTORC1 kinase activity in its GTP-bound state (8)(9)(10)(11)(12)(13)(14).Nutrient sensing is a key upstream signal for mTORC1 regulation, as growth factors or hormones are not sufficient to fully activate mTORC1 (9, 15). Whereas mTOR is dispersed within the cell upon amino acid starvation, amino acid replenishment redistributes mTOR to active, GTP-bound RHEB at the lysosomal surface (9). mTOR translocation is differentially regulated by the family of heterodimeric small Rag (Ras-related GTP binding) GTPases, which consists of four highly similar mammalian homologues (RagA, RagB, RagC, and RagD) (9,(16)(17)(18)(19). Recruitment of mTOR to the lysosome is promoted by GTP-bound RagA/B and GDP-bound RagC/D, whereas it is inhibited by GDP-bound RagA/B and GTP-bound RagC/D ...

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“…This may be due to the expression of other glutamine transporters in accordance with previous observations that mTORC1 can be reactivated by AA stimulation in HL-60 cells after SLC1A5 knockdown. 25,26 Because AML cells depend on glutamine for survival, we tested the effects of L-ase. This drug is essential in the treatment of acute lymphoid leukemias (ALLs) and induces a 60% of complete remission (CR) rate as a monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia

Willems

Jacque

Jacquel

et al. 2013

Blood

260

253

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Key Points• Glutamine removal and knockdown of the glutamine transporter SLC1A5 have antileukemic activity in AML.• The glutaminase activity of L-asparaginase inhibits mTORC1 and protein synthesis and induces a strong autophagy in AML.Cancer cells require nutrients and energy to adapt to increased biosynthetic activity, and protein synthesis inhibition downstream of mammalian target of rapamycin complex 1 (mTORC1) has shown promise as a possible therapy for acute myeloid leukemia (AML). Glutamine contributes to leucine import into cells, which controls the amino acid/Rag/mTORC1 signaling pathway. We show in our current study that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells. The knockdown of the SLC1A5 high-affinity transporter for glutamine induces apoptosis and inhibits tumor formation in a mouse AML xenotransplantation model. L-asparaginase (L-ase) is an anticancer agent also harboring glutaminase activity. We show that L-ases from both Escherichia coli and Erwinia chrysanthemi profoundly inhibit mTORC1 and protein synthesis and that this inhibition correlates with their glutaminase activity levels and produces a strong apoptotic response in primary AML cells. We further show that L-ases upregulate glutamine synthase (GS) expression in leukemic cells and that a GS knockdown enhances L-ase-induced apoptosis in some AML cells. Finally, we observe a strong autophagic process upon L-ase treatment. These results suggest that L-ase anticancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML. (Blood. 2013;122(20):3521-3532)

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SNAT2 transceptor signalling via mTOR: A role in cell growth and proliferation?

Cited by 36 publications

References 0 publications

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9

Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia

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