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HGNC Approved Gene Symbol: SLC3A2
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38): 11:62,856,109-62,888,860 (from NCBI)
Haynes et al. (1981) defined a monoclonal antibody variously called 4F2 and MDU1. (MDU1 is derived from 'monoclonal, Duke University.')
Lumadue et al. (1987) presented the cDNA-derived amino acid sequence of lymphocyte activation antigen 4F2. Their data indicate that the molecule is 529 amino acids long with an internal signal sequence and a single transmembrane domain. Because of the expression of the molecule on actively proliferating cells of various origins, including embryonic skin and lung, basal-layer keratinocytes, fibrosarcomas, osteosarcomas, and rhabdomyosarcomas, the 4F2 molecule may play a role in cell division.
Hemler and Strominger (1982) showed that 4F2 recognizes a determinant on the 65-kD polypeptide backbone of the heavy chain of an approximately 120-kD cell surface glycoprotein that also has a 40-kD unglycosylated light chain (SLC7A5; 600182).
Quackenbush et al. (1987) isolated a cDNA for the heavy chain. The sequence suggests that the heavy chain cDNA encodes a type II membrane glycoprotein. The cDNAs are derived from a single-copy gene that has been highly conserved during mammalian evolution.
Regulation of expression of the heavy chain gene was studied by Lindsten et al. (1988).
Posillico et al. (1985) demonstrated that the cell surface protein identified by 4F2 modulates intracellular calcium. It is a heteromeric glycoprotein with unique tissue distribution including activated T cells, neuroendocrine cells, and all malignant cell lines.
Michalak et al. (1986) showed that both the 44D7 and the 4F2 monoclonal antibodies inhibit specifically the sodium-dependent calcium fluxes characteristic of Na+/Ca(2+) exchanges of cardiac and skeletal muscle.
Quackenbush et al. (1987) reviewed the evidence pointing to a role of the 4F2 molecule in the regulation of intracellular calcium concentration and the concomitant control of growth, excitability, and endocrine secretion.
Amino acid transport across cellular plasma membranes depends on several parallel-functioning transporters and exchangers. The widespread transport system L accounts for a sodium-independent exchange of large neutral amino acids, whereas the system y(+)L exchanges positively charged amino acids and/or neutral amino acids together with sodium. The 4F2 heavy chain alone facilitates amino acid transport through both the L-type and the y(+)L-type systems, depending on the cellular system. Mastroberardino et al. (1998) identified the permease-related protein E16 (600182) as the first light chain of the 4F2 heavy chain and showed that the resulting heterodimeric complex mediates L-type amino acid transport. They hypothesized that at least one other related light chain may associate with the 4F2 heavy chain to produce a heterodimeric transporter with y(+)L transport characteristics.
The MDU1 gene is associated with endocrine cell function including that of pancreatic islet cells, thyroid C cells, and parathyroid cells (Posillico et al., 1987). Antibodies to the MDU1 cell surface glycoprotein modulate intracellular calcium and can stimulate parathyroid hormone secretion.
Sato et al. (1999) determined that uptake of cystine in Xenopus oocytes increased substantially when mouse xCT (607933) cRNA was coinjected with 4f2hc cRNA. Injection of either cRNA alone did not enhance uptake of cystine and glutamate.
Gottesdiener et al. (1988) showed that the gene for the heavy chain of 4F2 spans 8 kb and is composed of 9 exons. The 5-prime upstream region of the gene displays properties characteristic of housekeeping genes: it is GC rich and hypomethylated in peripheral blood lymphocyte DNA and contains multiple binding sites for the Sp1 transcription factor, while lacking TATA and CCAAT sequences. This region of the gene also displays sequence homologies with several other inducible T-cell genes, including interleukin-2, interleukin-2 receptor alpha chain, dihydrofolate reductase, thymidine kinase, and transferrin receptor genes.
Cryoelectron Microscopy
Yan et al. (2019) reported cryoelectron microscopy structures of the human LAT1 (SLC7A5; 600182)-4F2hc (SLC3A2) 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.
Peters et al. (1982) mapped the gene which codes the species-specific determinant defined by monoclonal antibody 4F2 to human chromosome 11. Hybrid human-mouse cell lines heterogeneous for 4F2 antigen expression were sorted using the fluorescence-activated cell sorter (FACS) to yield populations homogeneous with respect to the presence or absence of this determinant. FACS permits the rapid chromosome mapping of genes for cell surface antigens. Isozyme analysis showed that chromosome 11 markers were similarly present or absent. Assignment to chromosome 11 was confirmed by use of a hybrid line containing only this human chromosome. Immunoprecipitation of the 4F2 determinant from the '11 only' hybrid resulted in a heavy subunit of approximate molecular weight 100,000 and a light subunit of molecular weight 41,000. Antibody 4F2 is directed against the heavy chain only; hence, the origin of the light chain in the '11 only' cell line was unclear.
Francke et al. (1983) assigned the gene for 4F2 antigen to the long arm of chromosome 11. Two other antigens, called by them A3D8 and A1G3, mapped to the short arm of chromosome 11. Rochelle et al. (1992) indicated that the corresponding locus in the mouse is located on chromosome 19 near the centromere. Comparative mapping suggests that MDU1 is located in the proximal portion of 11q, perhaps 11q13. Courseaux et al. (1996) used a combination of methods to refine maps of an approximately 5-Mb region of 11q13. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Feral et al. (2005) found that Cd98hc null mouse cells were defective in integrin-dependent cell spreading and cell migration, and they showed increased sensitivity to anchorage deprivation-induced apoptosis. Furthermore, Cd98hc was required for efficient adhesion-induced activation of Akt (see 164730) and Rac (see 602048) GTPase. Cd98 promotes amino acid transport through its light chains; however, a Cd98hc mutant that could interact with beta-1 integrin (135630) but not with light chains restored integrin-dependent signaling and protection from apoptosis. In addition, Cd98hc null embryonic stem cells lost their tumorigenic potential in vivo.
Using cell culture and mice with deletion of Cd98hc in smooth muscle cells, Fogelstrand et al. (2009) showed that Cd98hc is markedly upregulated in neointimal and cultured vascular smooth muscle cells, and that activated, but not quiescent, vascular smooth muscle cells require Cd98hc for survival. In vivo, lack of Cd98hc does not affect normal vessel morphology but does reduce intimal hyperplasia after arterial injury. In vitro, loss of Cd98hc suppresses proliferation and induces apoptosis of vascular smooth muscle cells. Fogelstrand et al. (2009) concluded that CD98hc is important for vascular smooth muscle cell proliferation and survival and that activated vascular smooth muscle cells are physiologically dependent on CD98hc, indicating that CD98hc may be a therapeutic target for vasoocclusive disorders.
By specifically deleting Cd98 in mouse T cells, Cantor et al. (2011) prevented experimental autoimmune diabetes and reduced T-cell clonal expansion without impairing T-cell homing to pancreatic islets. Unlike Cd98 deletion in B lymphocytes, Cd98-null T cells showed only modestly impaired antigen-driven and homeostatic proliferation. Cd98-null T cells were activated by antigen, produced cytokines, and mediated efficient cell-mediated target cell lysis. Mutation analysis and generation of recombinant Cd98 showed that T-cell clonal expansion required the Cd98 integrin-binding domain. T cells bearing a Cd98 integrin-binding domain and expanded in vitro could adoptively transfer diabetes. Cantor et al. (2011) concluded that clonal expansion and the integrin-binding domain of CD98 are required for the pathogenesis of autoimmune disease.
Cantor, J., Slepak, M., Ege, N., Chang, J. T., Ginsberg, M. H. Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. J. Immun. 187: 851-860, 2011. [PubMed: 21670318] [Full Text: https://doi.org/10.4049/jimmunol.1100002]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Feral, C. C., Nishiya, N., Fenczik, C. A., Stuhlmann, H., Slepak, M., Ginsberg, M. H. CD98hc (SLC3A2) mediates integrin signaling. Proc. Nat. Acad. Sci. 102: 355-360, 2005. [PubMed: 15625115] [Full Text: https://doi.org/10.1073/pnas.0404852102]
Fogelstrand, P., Feral, C. C., Zargham, R., Ginsberg, M. H. Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2). J. Exp. Med. 206: 2397-2406, 2009. [PubMed: 19841087] [Full Text: https://doi.org/10.1084/jem.20082845]
Francke, U., Foellmer, B. E., Haynes, B. F. Chromosome mapping of human cell surface molecules: monoclonal anti-human lymphocyte antibodies 4F2, A3D8, and A1G3 define antigens controlled by different regions of chromosome 11. Somat. Cell Genet. 9: 333-344, 1983. [PubMed: 6190235] [Full Text: https://doi.org/10.1007/BF01539142]
Gottesdiener, K. M., Karpinski, B. A., Lindsten, T., Strominger, J. L., Jones, N. H., Thompson, C. B., Leiden, J. M. Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Molec. Cell. Biol. 8: 3809-3819, 1988. [PubMed: 3265470] [Full Text: https://doi.org/10.1128/mcb.8.9.3809-3819.1988]
Haynes, B. F., Hemler, M. E., Mann, D. L., Eisenbarth, G. S., Shelhamer, J., Mostowski, H. S., Thomas, C. A., Strominger, J. L., Fauci, A. S. Characterization of a monoclonal antibody (4F2) that binds to human monocytes and to a subset of activated lymphocytes. J. Immun. 126: 1409-1414, 1981. [PubMed: 7204970]
Hemler, M. E., Strominger, J. L. Characterization of antigen recognized by the monoclonal antibody (4F2): different molecular forms on human T and B lymphoblastoid cell lines. J. Immun. 129: 623-628, 1982. [PubMed: 6177771]
Lindsten, T., June, C. H., Thompson, C. B., Leiden, J. M. Regulation of 4F2 heavy-chain gene expression during normal human T-cell activation can be mediated by multiple distinct molecular mechanisms. Molec. Cell. Biol. 8: 3820-3826, 1988. [PubMed: 3265471] [Full Text: https://doi.org/10.1128/mcb.8.9.3820-3826.1988]
Lumadue, J. A., Glick, A. B., Ruddle, F. H. Cloning, sequence analysis, and expression of the large subunit of the human lymphocyte activation antigen 4F2. Proc. Nat. Acad. Sci. 84: 9204-9208, 1987. [PubMed: 3480538] [Full Text: https://doi.org/10.1073/pnas.84.24.9204]
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]
Michalak, M., Quackenbush, E. J., Letarte, M. Inhibition of Na+/Ca2+ exchanger activity in cardiac and skeletal muscle sarcolemmal vesicles by monoclonal antibody 44D7. J. Biol. Chem. 261: 92-95, 1986. [PubMed: 2416754]
Peters, P. G. M., Kamarck, M. E., Hemler, M. E., Strominger, J. L., Ruddle, F. H. Genetic and biochemical characterization of a human surface determinant on somatic cell hybrids: the 4F2 antigen. Somat. Cell Genet. 8: 825-834, 1982. [PubMed: 6187076] [Full Text: https://doi.org/10.1007/BF01543022]
Posillico, J. T., Srikanta, S., Brown, E. M., Eisenbarth, G. S. The 4F2 cell surface protein modulates intracellular calcium. (Abstract) Clin. Res. 33: 385A only, 1985.
Posillico, J. T., Srikanta, S., Eisenbarth, G., Quaranta, V., Kajiji, S., Brown, E. M. Binding of monoclonal antibody (4F2) to its cell surface antigen on dispersed adenomatous parathyroid cells raises cytosolic calcium and inhibits parathyroid hormone secretion. J. Clin. Endocr. Metab. 64: 43-50, 1987. [PubMed: 3782435] [Full Text: https://doi.org/10.1210/jcem-64-1-43]
Quackenbush, E., Clabby, M., Gottesdiener, K. M., Barbosa, J., Jones, N. H., Strominger, J. L., Speck, S., Leiden, J. M. 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. Proc. Nat. Acad. Sci. 84: 6526-6530, 1987. Note: Erratum: Proc. Nat. Acad. Sci. 84: 8618 only, 1987. [PubMed: 3476959] [Full Text: https://doi.org/10.1073/pnas.84.18.6526]
Rochelle, J. M., Watson, M. L., Oakey, R. J., Seldin, M. F. A linkage map of mouse chromosome 19: definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus. Genomics 14: 26-31, 1992. [PubMed: 1358795] [Full Text: https://doi.org/10.1016/s0888-7543(05)80278-2]
Sato, H., Tamba, M., Ishii, T., Bannai, S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274: 11455-11458, 1999. [PubMed: 10206947] [Full Text: https://doi.org/10.1074/jbc.274.17.11455]
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]