Genomes and Genes
large neutral amino acid transporter 1
Summary: A CD98 antigen light chain that when heterodimerized with CD98 antigen heavy chain (FUSION REGULATORY PROTEIN-1 HEAVY CHAIN) forms a protein that mediates sodium-independent L-type amino acid transport.
- Uchino H, Kanai Y, Kim D, Wempe M, Chairoungdua A, Morimoto E, et al. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol. 2002;61:729-37 pubmed..A substrate, however, becomes a blocker once Connolly accessible areas become large and/or the molecule has a high calculated logP value, such as those for melphalan, triiodothyronine, and thyroxine. ..
- Meier C, Ristic Z, Klauser S, Verrey F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J. 2002;21:580-9 pubmed
- Kobayashi H, Ishii Y, Takayama T. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J Surg Oncol. 2005;90:233-8 pubmed..These results suggest that LAT1 plays a significant role in cell proliferation, differentiation, and invasion in esophageal squamous cell carcinoma. ..
- Tamai S, Masuda H, Ishii Y, Suzuki S, Kanai Y, Endou H. Expression of L-type amino acid transporter 1 in a rat model of liver metastasis: positive correlation with tumor size. Cancer Detect Prev. 2001;25:439-45 pubmed..4 +/- 0.1%. A significant difference was noted between the two groups (P = .0004). We concluded that LAT1 plays an important role in tumor cell growth of liver metastatic tumors. ..
- Imai H, Kaira K, Oriuchi N, Yanagitani N, Sunaga N, Ishizuka T, et al. L-type amino acid transporter 1 expression is a prognostic marker in patients with surgically resected stage I non-small cell lung cancer. Histopathology. 2009;54:804-13 pubmed publisher..LAT1 expression is a promising pathological factor for predicting the prognosis in patients with resectable stage I NSCLC. ..
- Detta A, Cruickshank G. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors. Cancer Res. 2009;69:2126-32 pubmed publisher..Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy...
- Yamauchi K, Sakurai H, Kimura T, Wiriyasermkul P, Nagamori S, Kanai Y, et al. System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line. Cancer Lett. 2009;276:95-101 pubmed publisher..This potentiation may be used to reduce cisplatin exposure to alleviate many unwanted toxicity of the drug. ..
- Hosoya K, Kyoko H, Toyooka N, Kato A, Orihashi M, Tomi M, et al. Evaluation of amino acid-mustard transport as L-type amino acid transporter 1 (LAT1)-mediated alkylating agents. Biol Pharm Bull. 2008;31:2126-30 pubmed..These findings suggest that phenylglycine-mustard is a better substrate for LAT1 than melphalan and other amino acid-mustards. ..
- Kühne A, Kaiser R, Schirmer M, Heider U, Muhlke S, Niere W, et al. Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan. Pharmacogenet Genomics. 2007;17:505-17 pubmed..Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan. ..
- Zecevic M, Heitzmann D, Camargo S, Verrey F. SGK1 increases Na,K-ATP cell-surface expression and function in Xenopus laevis oocytes. Pflugers Arch. 2004;448:29-35 pubmed
- Kaneko S, Okuda Ashitaka E, Ando A, Nishimura K, Igarashi K, Maeda M, et al. Polyamines upregulate the mRNA expression of cationic amino acid transporter-1 in human retinal pigment epithelial cells. Am J Physiol Cell Physiol. 2007;293:C729-37 pubmed..These results suggest that spermine plays an important role in stimulation of mRNA expression of CAT-1, which is a crucial role in ornithine cytotoxicity in OAT-deficient hTERT-RPE cells. ..
- Killian D, Hermeling S, Chikhale P. Targeting the cerebrovascular large neutral amino acid transporter (LAT1) isoform using a novel disulfide-based brain drug delivery system. Drug Deliv. 2007;14:25-31 pubmed..Thus, the BTDS strategy may be utilized for rapid shuttling of various neuropharmaceuticals into brain. ..
- Ohno Y, Suda K, Masuko K, Yagi H, Hashimoto Y, Masuko T. Production and characterization of highly tumor-specific rat monoclonal antibodies recognizing the extracellular domain of human L-type amino-acid transporter 1. Cancer Sci. 2008;99:1000-7 pubmed publisher..Comparative immunohistochemical analyses of normal human tissues with anti-CD98 hc and anti-LAT1 revealed LAT1 to be an excellent molecular target for antibody therapy, possibly even superior to CD98 hc. ..
- Moret C, Dave M, Schulz N, Jiang J, Verrey F, Wagner C. Regulation of renal amino acid transporters during metabolic acidosis. Am J Physiol Renal Physiol. 2007;292:F555-66 pubmed..Our results suggest that the selective regulation of SNAT3 and y(+)LAT1 expression may serve a major role in the renal adaptation to acid secretion and thus for systemic acid-base balance. ..
- Kim S, Ahn Y, Yoon J, Kim H, Park S, Ahn S, et al. Expression of amino acid transporter LAT1 and 4F2hc in the healing process after the implantation of a tooth ash and plaster of Paris mixture. In Vivo. 2006;20:591-7 pubmed
- Pinho M, Serrão M, Jose P, Soares da Silva P. Organ specific underexpression renal of Na+-dependent B0AT1 in the SHR correlates positively with overexpression of NHE3 and salt intake. Mol Cell Biochem. 2007;306:9-18 pubmed..The regulation of B(0)AT1 gene transcription appears to be under the influence of Na(+) delivery, being organ specific. ..
- Mastroberardino L, Spindler B, Pfeiffer R, Skelly P, Loffing J, Shoemaker C, et al. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998;395:288-91 pubmed..The coexpression of h4F2hc is required for surface expression of these permease-related light chains, which belong to a new family of amino-acid transporters that form heterodimers with cell-surface glycoproteins. ..
- Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in stage I pulmonary adenocarcinoma. Lung Cancer. 2009;66:120-6 pubmed publisher..The overexpression of LAT1 and CD98 is a pathological factor to predict the prognosis in patients with resectable stage I pulmonary adenocarcinoma. ..
- Serbecic N, Lahdou I, Scheuerle A, Hoftberger R, Aboul Enein F. Function of the tryptophan metabolite, L-kynurenine, in human corneal endothelial cells. Mol Vis. 2009;15:1312-24 pubmed..Our data support that adequate levels of functional L-kynurenine might contribute to the maintenance of a relative immune privilege in the ocular anterior chamber, thereby contributing to the preservation of corneal allogeneic cells. ..
- Hirooka T, Fujiwara Y, Minami Y, Ishii A, Ishigooka M, Shinkai Y, et al. Cell-density-dependent methylmercury susceptibility of cultured human brain microvascular pericytes. Toxicol In Vitro. 2010;24:835-41 pubmed publisher..The susceptibility of the sparse pericytes is postulated to be due to the not only constitutively higher but also methylmercury-induced expression of LAT 1, which increased the intracellular accumulation of methylmercury. ..
- Fraga S, Pinho M, Soares da Silva P. Expression of LAT1 and LAT2 amino acid transporters in human and rat intestinal epithelial cells. Amino Acids. 2005;29:229-33 pubmed..In conclusion, Caco-2 and IEC-6 cells, as well as the rat intestinal mucosa, are endowed with both LAT1 and LAT2 amino acid transporter transcripts and protein. ..
- Maglott D, Durkin A, Lane S, Callen D, Feldblyum T, Nierman W. The gene for membrane protein E16 (D16S469E) maps to human chromosome 16q24.3 and is expressed in human brain, thymus, and retina. Genomics. 1994;23:303-4 pubmed
- Simmons Willis T, Koh A, Clarkson T, Ballatori N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J. 2002;367:239-46 pubmed..These transport proteins may therefore participate in metal ion homoeostasis and toxicity. ..
- Su T, Feng M, Weber M. Mediation of highly concentrative uptake of pregabalin by L-type amino acid transport in Chinese hamster ovary and Caco-2 cells. J Pharmacol Exp Ther. 2005;313:1406-15 pubmed..The differential affinity of PGB and GBP at L-type system leads to more concentrative accumulation of PGB than GBP, which may facilitate PGB transmembrane absorption in vivo. ..
- Boado R, Li J, Tsukamoto H, Pardridge W. Hypoxia induces de-stabilization of the LAT1 large neutral amino acid transporter mRNA in brain capillary endothelial cells. J Neurochem. 2003;85:1037-42 pubmed..These studies are consistent with post-transcriptional de-stabilization of the LAT1 large neutral amino acid transporter in hypoxia. ..
- Soares da Silva P, Serrão M. High- and low-affinity transport of L-leucine and L-DOPA by the hetero amino acid exchangers LAT1 and LAT2 in LLC-PK1 renal cells. Am J Physiol Renal Physiol. 2004;287:F252-61 pubmed
- Takabe W, Kanai Y, Chairoungdua A, Shibata N, Toi S, Kobayashi M, et al. Lysophosphatidylcholine enhances cytokine production of endothelial cells via induction of L-type amino acid transporter 1 and cell surface antigen 4F2. Arterioscler Thromb Vasc Biol. 2004;24:1640-5 pubmed..These findings suggest that an increase in uptake of neutral amino acids induced by LysoPC results in enhancement of inflammatory responses of endothelial cells. ..
- Bauch C, Forster N, Loffing Cueni D, Summa V, Verrey F. Functional cooperation of epithelial heteromeric amino acid transporters expressed in madin-darby canine kidney cells. J Biol Chem. 2003;278:1316-22 pubmed
- Shikano N, Kanai Y, Kawai K, Inatomi J, Kim D, Ishikawa N, et al. Isoform selectivity of 3-125I-iodo-alpha-methyl-L-tyrosine membrane transport in human L-type amino acid transporters. J Nucl Med. 2003;44:244-6 pubmed..95-fold higher than that via hLAT2 (P < 0.005). (125)I-IMT transport was hLAT1 selective. Investigations on the isoform selectivity of (125)I-IMT transport with other transporters are anticipated. ..
- Verrey F. System L: heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflugers Arch. 2003;445:529-33 pubmed..By mediating the regulated flux of these exchange substrates, unidirectional transporters control the activity of system L. ..
- Soares da Silva P, Serrao P, Fraga S, Pinho M. Expression and function of LAT1, a neutral amino acid exchanger, in renal porcine epithelial cell line LLC-PK. Acta Physiol Scand. 2005;185:71-8 pubmed..The density of transporter units in LLC-PK1 cells may be higher at the basolateral membranes, although be also present in the apical membranes. ..
- Karunakaran S, Umapathy N, Thangaraju M, Hatanaka T, Itagaki S, Munn D, et al. Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy. Biochem J. 2008;414:343-55 pubmed publisher..The blockade of ATB(0,+) in these cells with alpha-methyltryptophan is associated with cell cycle arrest. These studies reveal the potential of ATB(0,+) as a drug target for cancer chemotherapy. ..
- Ross D, Kim C, Tang G, Bohn O, Beck R, Ring B, et al. Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials. Clin Cancer Res. 2008;14:6602-9 pubmed publisher..Exploratory analysis suggests that this test will be most useful in clinical decision making for postmenopausal patients. ..
- Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. L-type amino acid transporter 1 (LAT1) is frequently expressed in thymic carcinomas but is absent in thymomas. J Surg Oncol. 2009;99:433-8 pubmed publisher..LAT1 is frequently expressed in thymic carcinomas but is absent in thymomas. Our results suggest that LAT1 expression might be an immunohistochemical marker for carcinomas, and could distinguish between thymomas and thymic carcinomas. ..
- Ring B, Seitz R, Beck R, Shasteen W, Soltermann A, Arbogast S, et al. A novel five-antibody immunohistochemical test for subclassification of lung carcinoma. Mod Pathol. 2009;22:1032-43 pubmed publisher..The results also suggest that if validated in prospectively defined clinical trials this classifier might identify candidates for targeted therapy that are overlooked with current diagnostic approaches. ..
- Nawashiro H, Otani N, Shinomiya N, Fukui S, Nomura N, Yano A, et al. The role of CD98 in astrocytic neoplasms. Hum Cell. 2002;15:25-31 pubmed..Several studies implicated the important role of LAT1 and 4F2hc in malignant transformation and carcinogenesis. The LAT1-CD98 pathway may represent a unique therapeutic target for cancer intervention. ..
- Vumma R, Wiesel F, Flyckt L, Bjerkenstedt L, Venizelos N. Functional characterization of tyrosine transport in fibroblast cells from healthy controls. Neurosci Lett. 2008;434:56-60 pubmed publisher..This study established fibroblast cells as a suitable experimental model for studying amino acid transport defects in humans. ..
- Haase C, Bergmann R, Fuechtner F, Hoepping A, Pietzsch J. 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. J Nucl Med. 2007;48:2063-71 pubmed..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. ..
- Jain Vakkalagadda B, Dey S, Pal D, Mitra A. Identification and functional characterization of a Na+-independent large neutral amino acid transporter, LAT1, in human and rabbit cornea. Invest Ophthalmol Vis Sci. 2003;44:2919-27 pubmed..A Na(+)-independent, facilitative transport system, LAT1, was identified and functionally characterized on rabbit cornea. LAT1 was also identified on human cornea. ..
- Kaper T, Looger L, Takanaga H, Platten M, Steinman L, Frommer W. Nanosensor detection of an immunoregulatory tryptophan influx/kynurenine efflux cycle. PLoS Biol. 2007;5:e257 pubmed..The strict coupling protects cells that overproduce IDO from kynurenine accumulation. Consequently, this mechanism may contribute to immunosuppression involved in autoimmunity and tumor immune escape. ..
- Atluri H, Talluri R, Mitra A. Functional activity of a large neutral amino acid transporter (LAT) in rabbit retina: a study involving the in vivo retinal uptake and vitreal pharmacokinetics of L-phenyl alanine. Int J Pharm. 2008;347:23-30 pubmed..Furthermore, based on these studies it can be concluded that LAT is involved in the retinal uptake and intravitreal elimination of L-Phe. ..
- Shennan D, Thomson J, Gow I, Travers M, Barber M. L-leucine transport in human breast cancer cells (MCF-7 and MDA-MB-231): kinetics, regulation by estrogen and molecular identity of the transporter. Biochim Biophys Acta. 2004;1664:206-16 pubmed..It is possible that LAT1 may be the major molecular correlate of system L in both cell types. However, not all of the properties of system L reflected those of LAT1/LAT2/CD98hc. ..
- Tomi M, Mori M, Tachikawa M, Katayama K, Terasaki T, Hosoya K. L-type amino acid transporter 1-mediated L-leucine transport at the inner blood-retinal barrier. Invest Ophthalmol Vis Sci. 2005;46:2522-30 pubmed..The objective of this study was to clarify the expression and function of LAT at the inner blood-retinal barrier (BRB)...
- Nagase K, Tomi M, Tachikawa M, Hosoya K. Functional and molecular characterization of adenosine transport at the rat inner blood-retinal barrier. Biochim Biophys Acta. 2006;1758:13-9 pubmed..The results of this study show that ENT2 most likely mediates adenosine transport at the inner BRB and is expected to play an important role in regulating the adenosine concentration in the retina. ..
- Jeong M, Kim C, Park J, Kim H, Ko Y, Park K, et al. Differential expression of system L amino acid transporters during wound healing process in the skin of young and old rats. Biol Pharm Bull. 2008;31:395-9 pubmed..These results suggest that the LAT1 and LAT2 increase in the wound healing process after cell injury in young and old rats, respectively. ..
- Matson C, Drewes L. Immunoblot detection of brain vascular proteins. Methods Mol Med. 2003;89:479-87 pubmed
- Boado R, Li J, Wise P, Pardridge W. Human LAT1 single nucleotide polymorphism N230K does not alter phenylalanine transport. Mol Genet Metab. 2004;83:306-11 pubmed..These studies demonstrate that the only known SNP in the open reading frame of human LAT1 has no effect on the kinetics of large neutral amino acid transport via this carrier. ..
- Loubière L, Vasilopoulou E, Bulmer J, Taylor P, Stieger B, Verrey F, et al. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta. 2010;31:295-304 pubmed publisher..Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit. ..
- Boado R, Li J, Chu C, Ogoshi F, Wise P, Pardridge W. Site-directed mutagenesis of cysteine residues of large neutral amino acid transporter LAT1. Biochim Biophys Acta. 2005;1715:104-10 pubmed publisher..These studies show that the Cys439 residue of LAT1 plays a significant role in either folding or insertion of the transporter protein in the plasma membrane...
- Fan X, Ross D, Arakawa H, Ganapathy V, Tamai I, Nakanishi T. Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors. Biochem Pharmacol. 2010;80:811-8 pubmed publisher..Our findings indicate that LAT1 expression is increased in human ovarian cancer cell lines; LAT1 may be a target for combination therapy with anti-proliferative aminopeptidase inhibitors to combat ovarian cancer. ..
- Fukushima D, Doi H, Katsura K, Ogawa N, Sekiguchi S, Fujimori K, et al. Glutamate exocrine dynamics augmented by plasma glutamine and the distribution of amino acid transporters of the rat pancreas. J Physiol Pharmacol. 2010;61:265-71 pubmed..The glutamate secretion into the PJ was augmented by plasma glutamine, indicating the de novo metabolisms of glutamate, together with the local expression of the related transporters. ..