The role of amino acid transporters in inherited and acquired diseases

Bröer, Stefan; Palacı́n, Manuel

doi:10.1042/bj20101912

Cited by 163 publications

(122 citation statements)

References 220 publications

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“…These results suggest that YAP/TAZ regulate expression of SLC7A5, while the effect on SLC3A2 is possibly due to an indirect effect on protein stability of SLC3A2 by dimer formation with SLC7A5. Consistent with this hypothesis, exogenous expression of an epithelial-specific transporter subunit SLC7A7 [38,39], which also complexes with SLC3A2 (Supplementary information, Figure S3B) but is not endogenously expressed in 293a cells, similarly increased SLC3A2 protein levels in Y/T dbKO cells ( Figure 2E). To determine whether the reduced Leu uptake in Y/T dbKO cells was due to the decreased expression of SLC7A5, we performed Leu uptake assays in the SLC7A5 re-expressing Y/T dbKO cells.…”

Section: Yap and Taz Regulate Leucine Uptake Via Slc7a5supporting

confidence: 65%

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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Section: Yap and Taz Regulate Leucine Uptake Via Slc7a5supporting

confidence: 65%

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

et al. 2015

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“…However, these transporters have kept the ability developed in bacteria to be upregulated in response to nutrient depletion, and in addition, some transporters are transcriptionally induced by HIFs in the nutrient-deprived tumor microenvironment (2,3). Among the many AA transporters identified in human physiology (34,35), at least three AA transporter systems have emerged as playing a major role in the control of growth and cancer aggressiveness if we consider their increased level of expression and correlation with poor disease prognosis. These are the bidirectional EAA transporter complex CD98/LAT1 (SLC5A7) induced by HIF2 (18) and apparently functionally "coupled" to the high-affinity glutamine transporter ASCT2 (SLC1A5; ref.…”

Section: Discussionmentioning

confidence: 99%

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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“…Transepithelial absorption across enterocytes involves then sequential transport across the luminal brushborder and basolateral membranes. The luminal step is mediated by the peptide transporter PEPT1 and various AA transporters Broer and Palacin 2011;Chillaron et al 2010;Daniel 2004). From enterocytes, amino acids are then released into the extracellular space by another set of AA transporters located in the basolateral membrane (Daniel and Kottra 2004).…”

Section: Introductionmentioning

confidence: 99%

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

et al. 2014

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Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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The role of amino acid transporters in inherited and acquired diseases

Cited by 163 publications

References 220 publications

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

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

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

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

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