Alternative titles; symbols
HGNC Approved Gene Symbol: SLC7A5
Cytogenetic location: 16q24.2 Genomic coordinates (GRCh38): 16:87,830,023-87,869,507 (from NCBI)
SLC7A5 is the primary leucine transporter in cells (Saito et al., 2019).
Gaugitsch et al. (1992) cloned a partial human E16 cDNA sequence that was expressed in activated lymphocytes. It was cloned by virtue of its AUUUA rapid degradation signal. Maglott et al. (1994) showed that the E16 gene is expressed abundantly in adult lung and liver, and is also expressed in human brain, thymus, retina, and some other tissues.
Kanai et al. (1998) used expression cloning to isolate a rat cDNA for Lat1.
Kanai et al. (1998) found that rat Lat1 was necessary for system-L amino acid transport, a major route by which cells import large neutral amino acids with branched or aromatic side chains.
Mastroberardino et al. (1998) identified the human E16 protein (GenBank AF077866) as the first light chain of 4F2 (158070), a cell surface glycoprotein, and showed that the resulting heterodimeric complex mediates L-type amino acid transport.
Suzuki et al. (2014) investigated how the high-affinity receptor for immunoglobulin E (see 147140) modulates the response of mast cells to a high- or low-affinity stimulus. Both high- and low-affinity stimuli elicited similar receptor phosphorylation; however, differences were observed in receptor cluster size, mobility, distribution, and the cells' effector responses. Low-affinity stimulation increased receptor association with the Src family kinase FGR (164940) and shifted signals from the adaptor LAT1 to the related adaptor LAT2 (605719). LAT1-dependent calcium signals required for mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced, altering immune cell recruitment at the site of inflammation.
Saito et al. (2019) identified SLC7A5 as a key regulator of proliferation in estrogen receptor (ER, or ESR1; 133430)-positive breast cancer cells. Knockdown of SLC7A5 in ER-positive cells impaired cell proliferation, whereas overexpression of SLC7A5 supported proliferation under leucine stress conditions. SLC7A5-knockdown MCF-7 cells did not form tumors when transplanted in mice, and parental MCF-7 tumors regressed markedly when treated with a selective SLC7A5 inhibitor. Under leucine stress conditions, the N-terminal half of LLGL2 (618483) interacted with SLC7A5 in cytoplasm, and LLGL2 transported SLC7A5 to the cell membrane. At the membrane, the C-terminal half of LLGL2 interacted with YKT6 (606209), forming a trimeric complex to facilitate membrane fusion and increase SLC7A5 levels at the surface for adaptation to nutrient stress conditions. An SLC7A5 inhibitor suppressed growth of tamoxifen-resistant MCF-7 cells, and knockdown of SLC7A5 restored tamoxifen sensitivity under leucine stress conditions. Overexpression of SLC7A5 in parental MCF-7 cells induced tamoxifen resistance under leucine stress conditions.
Najumudeen et al. (2021) showed that mice harboring both an oncogenic activating Kras (190070) mutation and an inactivating Apc (611731) mutation rewired their metabolism, increasing glutamine consumption in intestinal epithelium cells for proliferation. To meet the increased metabolic demand and sustain cell proliferation, the mutant cells upregulated Slc7a5. Slc7a5 was critical for maintaining intracellular amino acid levels following Apc and Kras mutations. Deletion of Slc7a5 reduced protein synthesis, altered the amino acid pool, and inhibited Mtor signaling, which resulted in sensitization of tumors and thereby suppressed colorectal tumor formation and reduced distant metastasis in mutant mice. Further analysis revealed that Slc7a5 was not only critical for early-stage colorectal tumorigenesis in mutant mice, but that it was also critical for development of late-stage intestinal adenocarcinoma and metastasis.
Cryoelectron Microscopy
Yan et al. (2019) reported cryoelectron microscopy structures of the human LAT1-4F2hc (SLC3A2; 158070) amino acid transporter complex alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 and 3.5 angstroms, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis revealed that 4F2hc is essential for the transport activity of the complex.
Maglott et al. (1994) mapped the E16 gene to chromosome 16q24.3 by use of a panel of mouse/human somatic cell hybrids.
Gaugitsch, H. W., Prieschl, E. E., Kalthoff, F., Huber, N. E., Baumruker, T. A novel transiently expressed, integral membrane protein linked to cell activation: molecular cloning via the rapid degradation signal AUUUA. J. Biol. Chem. 267: 11267-11273, 1992. [PubMed: 1597461]
Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda, H., Endou, H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273: 23629-23632, 1998. [PubMed: 9726963] [Full Text: https://doi.org/10.1074/jbc.273.37.23629]
Maglott, D. R., Durkin, A. S., Lane, S. A., Callen, D. F., Feldblyum, T. V., Nierman, W. C. The gene for membrane protein E16 (D16S469E) maps to human chromosome 16q24.3 and is expressed in human brain, thymus, and retina. Genomics 23: 303-304, 1994. [PubMed: 7829099] [Full Text: https://doi.org/10.1006/geno.1994.1504]
Mastroberardino, L., Spindler, B., Pfeiffer, R., Skelly, P. J., Loffing, J., Shoemaker, C. B., Verrey, F. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395: 288-291, 1998. [PubMed: 9751058] [Full Text: https://doi.org/10.1038/26246]
Najumudeen, A. K., Ceteci, F., Fey, S. K., Hamm, G., Steven, R. T., Hall, H., Nikula, C. J., Dexter, A., Murta, T., Race, A. M., Sumpton, D., Vlahov, N., and 31 others. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nature Genet. 53: 16-26, 2021. [PubMed: 33414552] [Full Text: https://doi.org/10.1038/s41588-020-00753-3]
Saito, Y., Li, L., Coyaud, E., Luna, A., Sander, C., Raught, B., Asara, J. M., Brown, M., Muthuswamy, S. K. LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer. Nature 569: 275-279, 2019. [PubMed: 30996345] [Full Text: https://doi.org/10.1038/s41586-019-1126-2]
Suzuki, R., Leach, S., Liu, W., Ralston, E., Scheffel, J., Zhang, W., Lowell, C. A., Rivera, J. Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 343: 1021-1025, 2014. [PubMed: 24505132] [Full Text: https://doi.org/10.1126/science.1246976]
Yan, R., Zhao, X., Lei, J., Zhou, Q. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature 568: 127-130, 2019. [PubMed: 30867591] [Full Text: https://doi.org/10.1038/s41586-019-1011-z]