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Gene Review

SLC3A2  -  solute carrier family 3 (amino acid...

Homo sapiens

Synonyms: 4F2, 4F2 cell-surface antigen heavy chain, 4F2 heavy chain antigen, 4F2HC, 4F2hc, ...
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Disease relevance of SLC3A2

  • LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells [1].
  • We found that the mRNAs of 4F2hc and hLAT1 were expressed in the human placenta and a human choriocarcinoma cell line [2].
  • The b(0,+)AT transporter which associates with the 4F2hc-related rBAT protein to form the luminal high-affinity diamino acid transporter defective in cystinuria, belongs to the same family of glycoprotein-associated amino acid transporters (gpaATs) [3].
  • In addition, the specific inhibition of LAT1 and 4F2hc might be a new rationale to suppress oral cancer progression [4].
  • Integrin-CD98 association was established by reciprocal immunoprecipitation experiments, and confirmed by CD98-induced clustering of alpha3beta1 but not alpha4beta1 on the surface of rhabdomyosarcoma cells [5].

High impact information on SLC3A2

  • The expression of rBAT and 4F2hc induces system b[0,+] and system y+ L activity in Xenopus laevis oocytes, respectively [6].
  • The molecular nature of these transporters remains unknown, although expression of the human cell-surface glycoprotein 4F2 heavy chain (h4F2hc; CD98 in the mouse) is known to induce low levels of L- and/or y(+)L-type transport [7].
  • CD98, an early T-cell activation antigen that associates with functional integrins, was found to regulate integrin activation [8].
  • These data indicate that CD98 is involved in regulating integrin affinity, and validate an unbiased genetic approach to analysing integrin signalling pathways [8].
  • Furthermore, antibody-mediated crosslinking of CD98 stimulated beta1 integrin-dependent cell adhesion [8].

Chemical compound and disease context of SLC3A2


Biological context of SLC3A2

  • To better understand the molecular mechanism(s) that controls 4F2HC gene expression in both resting and activated T cells, a 4F2HC human genomic clone was isolated and structurally characterized [10].
  • The 4F2HC gene spans 8 kilobases of chromosome 11 and is composed of nine exons [10].
  • A 255-base-pair fragment of the 4F2HC gene which contains 154 base pairs of the 5' flanking sequence was able to efficiently promote expression of the bacterial chloramphenicol acetyltransferase gene in human Jurkat T cells, indicating that it contains promoter or enhancer (or both) sequences [10].
  • CD98 is expressed on both hematopoietic and nonhematopoietic cells and has been implicated in a variety of different aspects of cell physiology and immunobiology [11].
  • The levels of the 4F2hc and hLAT1 proteins in the human placenta increased at full term compared with those at midtrimester [2].

Anatomical context of SLC3A2

  • By contrast, system B(0+), associated with system y(+)L (SLC3A2/SLC7A7 and SLC7A6), made a major contribution to the transport of cationic amino acids in pachytene spermatocytes and early spermatids [12].
  • Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation [10].
  • The high expression of LAT-2 mRNA in epithelial cells of proximal tubules, the basolateral location of 4F2hc in these cells, and the amino acid transport activity of LAT-2 suggest that this transporter contributes to the renal reabsorption of neutral amino acids in the basolateral domain of epithelial proximal tubule cells [13].
  • Transport characteristics of asc-1 were assessed by coexpression with 4F2hc in Xenopus oocytes and HeLa cells [14].
  • 4F2hc is necessary for trafficking of the light chain to the plasma membrane, whereas the light chains are thought to determine the transport characteristics of the respective heterodimer [15].

Associations of SLC3A2 with chemical compounds


Physical interactions of SLC3A2

  • The homology data and the expression pattern are in agreement with the hypothesis that SLC7A8 represents a novel light chain interacting with the 4F2 heavy chain in the multimeric complex mediating neutral and/or cationic amino acid transport and cystine/glutamate exchange [20].
  • There is new evidence that the functional unit of system y+L amino acid transporter is a disulfide bridge-dependent complex of 4F2hc with a Xenopus oocyte plasma membrane protein [21].
  • CD98 and mutants that interacted with beta1 integrins increased both focal adhesion formation and FAK and AKT phosphorylation [22].
  • The 4F2hc/LAT1 complex has been suggested to be the most important molecular component responsible for this transport [23].
  • Surprisingly, xCT transport activity in HEK293 cells is not dependent on the co-expression of the exogenous 4F2hc [24].

Regulatory relationships of SLC3A2

  • When human xCT was co-expressed with 4F2hc, the former localised to the oocyte plasma membrane [19].
  • CD98-induced cell adhesion and migration was inhibited by addition of phosphoinositol 3-OH kinase (PI3-K) inhibitors suggesting these cell functions are PI3-K-dependent [22].
  • Binding of monoclonal antibody (4F2) to its cell surface antigen on dispersed adenomatous parathyroid cells raises cytosolic calcium and inhibits parathyroid hormone secretion [25].

Other interactions of SLC3A2

  • These data suggest that LAT-2 is an additional member of the family of 4F2 light chain subunits, which associates with 4F2hc to express a system L transport activity with broad specificity for zwitterionic amino acids [13].
  • Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance [17].
  • In 1992, rBAT and 4F2hc (genes SLC3A1 and SLC3A2, respectively, in the nomenclature of the Human Genome Organization) were identified as putative heavy subunits of mammalian amino acid transporters [26].
  • Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc- [19].
  • BeWo cells express both heavy (4F2hc) and light (LAT1, LAT2) chains of the System L holotransporter [27].

Analytical, diagnostic and therapeutic context of SLC3A2


  1. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Nawashiro, H., Otani, N., Shinomiya, N., Fukui, S., Ooigawa, H., Shima, K., Matsuo, H., Kanai, Y., Endou, H. Int. J. Cancer (2006) [Pubmed]
  2. Expression and regulation of 4F2hc and hLAT1 in human trophoblasts. Okamoto, Y., Sakata, M., Ogura, K., Yamamoto, T., Yamaguchi, M., Tasaka, K., Kurachi, H., Tsurudome, M., Murata, Y. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  3. New glycoprotein-associated amino acid transporters. Verrey, F., Jack, D.L., Paulsen, I.T., Saier, M.H., Pfeiffer, R. J. Membr. Biol. (1999) [Pubmed]
  4. Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in oral squamous cell carcinoma and its precusor lesions. Kim, d.o. .K., Ahn, S.G., Park, J.C., Kanai, Y., Endou, H., Yoon, J.H. Anticancer Res. (2004) [Pubmed]
  5. Beta1 integrins show specific association with CD98 protein in low density membranes. Kolesnikova, T.V., Mannion, B.A., Berditchevski, F., Hemler, M.E. BMC Biochem. (2001) [Pubmed]
  6. Transporters for cationic amino acids in animal cells: discovery, structure, and function. Devés, R., Boyd, C.A. Physiol. Rev. (1998) [Pubmed]
  7. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Mastroberardino, L., Spindler, B., Pfeiffer, R., Skelly, P.J., Loffing, J., Shoemaker, C.B., Verrey, F. Nature (1998) [Pubmed]
  8. Complementation of dominant suppression implicates CD98 in integrin activation. Fenczik, C.A., Sethi, T., Ramos, J.W., Hughes, P.E., Ginsberg, M.H. Nature (1997) [Pubmed]
  9. Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by alpha3beta1 integrin and regulated by insulin-like growth factor-1 and CD98. Chandrasekaran, S., Guo, N.H., Rodrigues, R.G., Kaiser, J., Roberts, D.D. J. Biol. Chem. (1999) [Pubmed]
  10. Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Gottesdiener, K.M., Karpinski, B.A., Lindsten, T., Strominger, J.L., Jones, N.H., Thompson, C.B., Leiden, J.M. Mol. Cell. Biol. (1988) [Pubmed]
  11. The functional interactions between CD98, beta1-integrins, and CD147 in the induction of U937 homotypic aggregation. Cho, J.Y., Fox, D.A., Horejsi, V., Sagawa, K., Skubitz, K.M., Katz, D.R., Chain, B. Blood (2001) [Pubmed]
  12. Multiple pathways for cationic amino Acid transport in rat seminiferous tubule cells. Cérec, V., Piquet-Pellorce, C., Aly, H.A., Touzalin, A.M., Jégou, B., Bauché, F. Biol. Reprod. (2007) [Pubmed]
  13. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. Pineda, M., Fernández, E., Torrents, D., Estévez, R., López, C., Camps, M., Lloberas, J., Zorzano, A., Palacín, M. J. Biol. Chem. (1999) [Pubmed]
  14. The amino acid transporter asc-1 is not involved in cystinuria. Pineda, M., Font, M., Bassi, M.T., Manzoni, M., Borsani, G., Marigo, V., Fernández, E., Río, R.M., Purroy, J., Zorzano, A., Nunes, V., Palacín, M. Kidney Int. (2004) [Pubmed]
  15. Function and structure of heterodimeric amino acid transporters. Wagner, C.A., Lang, F., Bröer, S. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  16. CD98hc (SLC3A2) mediates integrin signaling. Feral, C.C., Nishiya, N., Fenczik, C.A., Stuhlmann, H., Slepak, M., Ginsberg, M.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance. Torrents, D., Estévez, R., Pineda, M., Fernández, E., Lloberas, J., Shi, Y.B., Zorzano, A., Palacín, M. J. Biol. Chem. (1998) [Pubmed]
  18. Transcriptional regulation of the LAT-1/CD98 light chain. Padbury, J.F., Diah, S.K., McGonnigal, B., Miller, C., Fugere, C., Kuzniar, M., Thompson, N.L. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  19. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-. Bassi, M.T., Gasol, E., Manzoni, M., Pineda, M., Riboni, M., Martín, R., Zorzano, A., Borsani, G., Palacín, M. Pflugers Arch. (2001) [Pubmed]
  20. SLC7A8, a gene mapping within the lysinuric protein intolerance critical region, encodes a new member of the glycoprotein-associated amino acid transporter family. Bassi, M.T., Sperandeo, M.P., Incerti, B., Bulfone, A., Pepe, A., Surace, E.M., Gattuso, C., De Grandi, A., Buoninconti, A., Riboni, M., Manzoni, M., Andria, G., Ballabio, A., Borsani, G., Sebastio, G. Genomics (1999) [Pubmed]
  21. Cystinuria calls for heteromultimeric amino acid transporters. Palacín, M., Estévez, R., Zorzano, A. Curr. Opin. Cell Biol. (1998) [Pubmed]
  22. CD98 modulates integrin beta1 function in polarized epithelial cells. Cai, S., Bulus, N., Fonseca-Siesser, P.M., Chen, D., Hanks, S.K., Pozzi, A., Zent, R. J. Cell. Sci. (2005) [Pubmed]
  23. Inter-individual variation in brain phenylalanine concentration in patients with PKU is not caused by genetic variation in the 4F2hc/LAT1 complex. Møller, L.B., Paulsen, M., Koch, R., Moats, R., Guldberg, P., Güttler, F. Mol. Genet. Metab. (2005) [Pubmed]
  24. xCt cystine transporter expression in HEK293 cells: pharmacology and localization. Shih, A.Y., Murphy, T.H. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  25. Binding of monoclonal antibody (4F2) to its cell surface antigen on dispersed adenomatous parathyroid cells raises cytosolic calcium and inhibits parathyroid hormone secretion. Posillico, J.T., Srikanta, S., Eisenbarth, G., Quaranta, V., Kajiji, S., Brown, E.M. J. Clin. Endocrinol. Metab. (1987) [Pubmed]
  26. Heteromeric amino acid transporters explain inherited aminoacidurias. Palacín, M., Bertran, J., Zorzano, A. Curr. Opin. Nephrol. Hypertens. (2000) [Pubmed]
  27. Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Ritchie, J.W., Taylor, P.M. Biochem. J. (2001) [Pubmed]
  28. Cloning, sequence analysis, and expression of the large subunit of the human lymphocyte activation antigen 4F2. Lumadue, J.A., Glick, A.B., Ruddle, F.H. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  29. Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth. Quackenbush, E., Clabby, M., Gottesdiener, K.M., Barbosa, J., Jones, N.H., Strominger, J.L., Speck, S., Leiden, J.M. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  30. Manipulation of CD98 expression affects both trophoblast cell fusion and amino acid transport activity during syncytialization of human placental BeWo cells. Kudo, Y., Boyd, C.A., Millo, J., Sargent, I.L., Redman, C.W. J. Physiol. (Lond.) (2003) [Pubmed]
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