Identification of LAT4, a Novel Amino Acid Transporter with System L Activity

Bodoy, Susanna; Martín, Lorena; Zorzano, António; Palacı́n, Manuel; Estévez, Raúl; Bertran, Joan

doi:10.1074/jbc.m408638200

Cited by 221 publications

(233 citation statements)

References 42 publications

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“…Recently, LAT3 (solute carrier 43) was identified, and several properties distinguish LAT3 from LAT1 and LAT2. For example, LAT3 does not require coexpression with 4F2hc and further exhibits a narrow substrate selectivity, preferring phenylalanine to others as substrates (17). Recently, LAT4 (solute carrier 43) was shown to have transport activity similar to that of LAT3 but a different tissue distribution (17).…”

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confidence: 99%

L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo

Haase¹,

Bergmann²,

Fuechtner³

et al. 2007

Journal of Nuclear Medicine

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Expression of system L amino acid transporters (LAT) is strongly increased in many types of tumor cells. The purpose of this study was to demonstrate that 18 F-labeled amino acids, for example, 3-O-methyl-6-18 F-fluoro-L-dopa ( 18 F-OMFD), that accumulate in tumors via LAT represent an important class of imaging agents for visualization of tumors in vivo by PET. Methods: 18 F-OMFD uptake kinetics, transport inhibition, and system L messenger RNA expression were studied in vitro in human adenocarcinoma (HT-29), squamous cell carcinoma (FaDu), macrophages (THP-1), and primary aortic endothelial cells (HAEC) and in vivo in the corresponding mouse tumor xenograft models. Results: Uptake of 18 F-OMFD in all cell lines tested was mediated mainly by the sodium-independent high-capacity LAT. We found higher uptake in FaDu cells (V max , 10.6 6 1.1 nmol/min · mg of cell protein) and in the corresponding FaDu tumor xenografts than in the other cells and corresponding xenograft models studied. Quantitative messenger RNA analysis revealed that tumor cells and xenografts have a higher expression of LAT1 than do HAEC and THP-1 macrophages. However, only in the FaDu tumor model did an increased 18 F-OMFD uptake seem to be explained by increased LAT expression. Furthermore, we demonstrated a high expression of LAT4, a recently identified LAT. Conclusion: Our findings support the hypothesis that 18 F-OMFD is a tracer for visualization of tumor cells. 18 F-OMFD particularly seems to be a suitable tracer for diagnostic imaging of amino acid transport in poorly differentiated squamous cell head and neck carcinoma with increased LAT1 and LAT4 expression.

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L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo

Haase¹,

Bergmann²,

Fuechtner³

et al. 2007

Journal of Nuclear Medicine

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“…But as a heterodimer with the 4F2hc antigen which is a single-membrane-spanning protein, Lat1 is capable of amino acid activity as characterized system L. 4F2hc was reportedly necessary for trafficking of the light chain (Lat1) to the plasma membrane, whereas the light chain is thought to determine the transport characteristics [26]. Until now, 4 isotypes of Lats were reported [1,2,23]. Among them, Lat1 drew special attention because cancer cells possessed potent Lat1 expression, whereas normal cells did not [18,22].…”

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Canine Lat1: Molecular Structure, Distribution and Its Expression in Cancer Samples

Ochiai

Morishita

Onda

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. A full-length cDNA sequence of canine L-type amino acid transporter 1 (Lat1) was determined from a canine brain. The sequence was 1828 bp long and was predicted to encode 485 amino acid polypeptides. The deduced amino acid sequence of canine Lat1 showed 93.2% and 91.1% similarities to those of humans and rats, respectively. Northern blot analysis detected Lat1 expression in the cerebellum at 4 kb, and Western blot analysis showed a single band at 40 kDa. RT-PCR analysis revealed a distinct expression of Lat1 in the pancreas and testis in addition to the cerebrum and cerebellum. Notably, Lat1 expression was observed in the tissues of thyroid cancer, melanoma and hemangiopericytoma. Although the cancer samples examined were not enough, Lat1 may serve as a useful biomarker of cancer cells in veterinary clinic.

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“…32 Expression of LAT2 has been shown in the epithelium of kidney proximal tubules and the digestive tract. [33][34][35][36][37] LAT3 and LAT4 have been localized to the apical plasma membrane of podocytes 38 and the distal tubules and collecting ducts, 39 respectively. In the present study, we have used a rat model of CGN to investigate the activation of mTORC1 pathway as a possible underlying factor in the crescent formation of glomerular epithelial cells.…”

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Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Identification of LAT4, a Novel Amino Acid Transporter with System L Activity

Cited by 221 publications

References 42 publications

L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo

L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo

Canine Lat1: Molecular Structure, Distribution and Its Expression in Cancer Samples

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

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