LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation

Milkereit, Ruth; Persaud, Avinash K.; Vanoaica, Liviu; Guetg, Adriano; Verrey, François; Rotin, Daniela

doi:10.1038/ncomms8250

Cited by 171 publications

(169 citation statements)

References 24 publications

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“…Finally, recent work by Milkereit and colleagues suggested a novel mechanism based on leucine lysosomal sensing (40). This last mechanism is particularly appealing in the context of this study, as LAT1 might be the first AA transporter to have two distinct chaperones, CD98 for plasma membrane and LAPTM4b for LAT1 lysosomal membrane expression (40). This finding of dual LAT1 expression could explain the extreme mTORC1 inhibition and growth defects of LAT1 KO cells, contrasting with the nonaffected CD98 KO cells.…”

Section: Lat1: a Dual Cytosolic/lysosomal Leucine Transporter?mentioning

confidence: 80%

“…Wolfson and colleagues provided evidence that sestrin2 is responsible for cytoplasmic leucine sensing and mTORC1 activation (39). Finally, recent work by Milkereit and colleagues suggested a novel mechanism based on leucine lysosomal sensing (40). This last mechanism is particularly appealing in the context of this study, as LAT1 might be the first AA transporter to have two distinct chaperones, CD98 for plasma membrane and LAPTM4b for LAT1 lysosomal membrane expression (40).…”

Section: Lat1: a Dual Cytosolic/lysosomal Leucine Transporter?mentioning

confidence: 81%

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Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

et al. 2016

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The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target. This complex promotes tumorigenesis with CD98 (4F2hc) engaging b-integrin signaling while LAT1 (SLC7A5) imports essential amino acids (EAA) and promotes mTORC1 activity. However, it is unclear as to which member of the heterodimer carries the most prevalent protumoral action. To answer this question, we explored the tumoral potential of each member by gene disruption of CD98, LAT1, or both and by inhibition of LAT1 with the selective inhibitor (JPH203) in six human cancer cell lines from colon, lung, and kidney. Each knockout respectively ablated 90% (CD98 KO ) and 100% (LAT1 KO ) of Na þ -independent leucine transport activity. LAT1 KO or JPH203-treated cells presented an amino acid stress response with ATF4, GCN2 activation, mTORC1 inhibition, and severe in vitro and in vivo tumor growth arrest. We show that this severe growth phenotype is independent of the level of expression of CD98 in the six tumor cell lines. Surprisingly, CD98KO cells with only 10% EAA transport activity displayed a normal growth phenotype, with mTORC1 activity and tumor growth rate undistinguishable from wild-type cells. However, CD98KO cells became extremely sensitive to inhibition or genetic disruption of LAT1 (CD98 KO /LAT1 KO ). This finding demonstrates that the tumoral potential of CD98 KO cells is due to residual LAT1 transport activity. Therefore, these findings clearly establish that LAT1 transport activity is the key growthlimiting step of the heterodimer and advocate the pharmacology development of LAT1 transporter inhibitors as a very promising anticancer target. Cancer Res; 76(15);

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Section: Lat1: a Dual Cytosolic/lysosomal Leucine Transporter?mentioning

confidence: 80%

Section: Lat1: a Dual Cytosolic/lysosomal Leucine Transporter?mentioning

confidence: 81%

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

et al. 2016

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“…The Gln transporter SLC1A5 in the plasma membrane is another candidate sensor for priming amino acids. Its activity is in some cells required for Gln to promote mTORC1 activation by Leu (20), possibly by supplying cytoplasmic Gln for Gln/Leu antiport (20,43).…”

Section: Discussionmentioning

confidence: 99%

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism

Dyachok

Earnest²,

Iturraran

et al. 2016

Journal of Biological Chemistry

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The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes L-asparagine, L-glutamine, L-threonine, L-arginine, L-glycine, L-proline, L-serine, L-alanine, and L-glutamic acid. The group of activating amino acids is dominated by L-leucine but also includes L-methionine, L-isoleucine, and L-valine. L-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation.

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“…The dimeric LAT1 transporter complex functions at the plasma membrane (PM) [26,33,34], as well as at the lysosome [37]. To exclude the possibility that LAT1 mislocalization may contribute to the reduced Leu uptake in Y/T dbKO cells, we examined the LAT1 cellular localization.…”

Section: Yap and Taz Regulate Leucine Uptake Via Slc7a5mentioning

confidence: 99%

The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

et al. 2015

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YAP and TAZ are transcriptional co-activators and function as the major effectors of the Hippo tumor suppressor pathway, which controls cell growth, tissue homeostasis, and organ size. Here we show that YAP/TAZ play an essential role in amino acid-induced mTORC1 activation, particularly under nutrient-limiting conditions. Mechanistically, YAP/TAZ act via the TEAD transcription factors to induce expression of the high-affinity leucine transporter LAT1, which is a heterodimeric complex of SLC7A5 and SLC3A2. Deletion of YAP/TAZ abolishes expression of LAT1 and reduces leucine uptake. Re-expression of SLC7A5 in YAP/TAZ knockout cells restores leucine uptake and mTORC1 activation. Moreover, SLC7A5 knockout cells phenocopies YAP/TAZ knockout cells which exhibit defective mTORC1 activation in response to amino acids. We further demonstrate that YAP/TAZ act through SLC7A5 to provide cells with a competitive growth advantage. Our study provides molecular insight into the mechanism of YAP/TAZ target genes in cell growth regulation.

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LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation

Cited by 171 publications

References 24 publications

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism

The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

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