Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines
Open accessAbstract
System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a critical role in cell growth and proliferation. In the present study, we have examined the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examined express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds.
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Intracellular glutamine may facilitate import of a broad range of LAT1 substrates including leucine, isoleucine, valine, methionine, tyrosine, tryptophan, and phenylalanine.
“In such a manner, intracellular glutamine may facilitate the import of a broad range of LAT1 substrates, including leucine, isoleucine, valine, methionine, tyrosine, tryptophan and phenylalanine”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Yanagida et al., 2001
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- Authors
- Yanagida, O., Kanai, Y., Chairoungdua, A., Kim, D. K., Segawa, H., Nii, T., Cha, S. H., Matsuo, H., Fukushima, J.-I., Fukasawa, Y., Tani, Y., Taketani, Y., Uchino, H., Kim, J. Y., Inatomi, J., Okayasu, I., Miyamoto, K.-I., Takeda, E., Goya, T., & Endou, H.
- Affiliations
- Kyorin University (JP)
- Tokushima University (JP)
- Kanazawa University (JP)
- Kitasato University (JP)
- Venue
- Biochimica et Biophysica Acta (BBA) - Biomembranes
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 1514
- Issue
- 2
- Pages
- 291-302
- ISSN
- 0005-2736 (ISSN-L)
- OpenAlex
- W2040329518
- Cited by
- 746
- References
- 54
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 38 · 2023: 35 · 2022: 41 · 2021: 51 · 2020: 49 · 2019: 42 · 2018: 40 · 2017: 36 · 2016: 36 · 2015: 34 · 2014: 33 · 2013: 31 · 2012: 27
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Biomembranes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Toyota Physical and Chemical Research Institute
- Japan Foundation for Applied Enzymology
- Promotion and Mutual Aid Corporation for Private Schools of Japan
- Japan Science and Technology Corporation
- Japan Health Sciences Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant nutrient uptake and metabolism
- Keywords
- LAT1, system L, cancer cell lines, amino acid substitutions, disulfide bonds, N-glycosylation, tissue expression, leukemia cell lines, essential amino acids
- MeSH terms
- Amino Acids, Essential, Animals, Carrier Proteins, Fetus, Humans, Molecular Sequence Data, Oocytes, RNA, Messenger, Substrate Specificity, Protein Biosynthesis, Tumor Cells, Cultured, Xenopus, DNA Probes, Antigens, CD, RNA, Complementary, DNA, Complementary, Amino Acid Transport Systems, Fusion Regulatory Protein-1
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