Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Laura R. de La Ballina
  • Tomás de Garay
  • Chloé C. Féral
  • Manuel Palacín
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101895


Historical Background

The ability of cells to sense, respond, and adapt to their environment is essential for multicellular life. SLC3A2 protein provides cells with the capacity of adjusting to their surroundings by mediating two fundamental molecular functions: amino acid transport and integrin signaling.

SLC3A2 is involved in many cellular processes, such as early activation of T and B cells (Cantor et al. 2009, 2012), cell fusion (Deves et al. 2000; Takesono et al. 2012), cell survival and migration (Feral et al. 2005), cell proliferation (Cantor et al. 2009; Boulter et al. 2013; de la Ballina et al. 2016), mechanotransduction (Estrach et al. 2014), and angiogenesis ( Liao et al. 2016). Thus, SLC3A2 is crucial for responding to different cellular stresses (i.e., oxidative or nutritional stress (de la Ballina et al. 2016),...

This is a preview of subscription content, log in to check access.


  1. Bajaj J, Konuma T, Lytle N, Kwon H, Ablack J, Cantor J, Rizzieri D, Chuah C, Oehler V, Broome E, Ball E, van der Horst E, Ginsberg M, Reya T, et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell. 2016;30:792–805. doi:10.1016/j.ccell.2016.10.00330.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Borsani G, Bassi MT, Sperandeo MP, De Grandi A, Buoninconti A, Riboni M, Manzoni M, Incerti B, Pepe A, Andria G, Ballabio A, Sebastio G, et al. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat Genet. 1999;21:297–301. doi:10.1038/681521.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Boulter E, Estrach S, Errante A, Pons C, Cailleteau L, Tissot F, Meneguzzi G, Féral CC, et al. CD98hc (SLC3A2) regulation of skin homeostasis wanes with age. J Exp Med. 2013;210:173–90. doi:10.1084/jem.20121651210.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bröer S, Wagner CA, et al. Structure-function relationships of heterodimeric amino acid transporters. Cell Biochem Biophys. 2002;36:155–68. doi:10.1385/CBB:36:2-3:15536.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cantor J, Browne CD, Ruppert R, Féral CC, Fässler R, Rickert RC, Ginsberg MH, et al. CD98hc facilitates B cell proliferation and adaptive humoral immunity. Nat Immunol. 2009;10:412–9. doi:10.1038/ni.171210.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cantor JM, Ginsberg MH, et al. CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci. 2012;125:1373–82. doi:10.1242/jcs.096040125.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cibrian D, Saiz ML, de la Fuente H, Sánchez-Díaz R, Moreno-Gonzalo O, Jorge I, Ferrarini A, Vázquez J, Punzón C, Fresno M, Vicente-Manzanares M, Daudén E, Fernández-Salguero PM, Martín P, Sánchez-Madrid F, et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat Immunol. 2016;17:985–96. doi:10.1038/ni.350417.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutté E, Massard PA, de la Ballina LR, Endou H, Wempe MF, Palacin M, Parks SK, Pouyssegur J, et al. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res. 2016;76:4481–92. doi:10.1158/0008-5472.CAN-15-337676.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Deves R, Boyd CAR, et al. Surface antigen CD98 (4F2): not a single membrane protein, but a family of proteins with multiple functions. J Membr Biol. 2000;173:165–77.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. doi:10.1016/j.cell.2012.03.042149.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Domínguez F, Simón C, Quiñonero A, Ramírez MÁ, González-Muñoz E, Burghardt H, Cervero A, Martínez S, Pellicer A, Palacín M, Sánchez-Madrid F, Yáñez-Mó M, et al. Human endometrial CD98 is essential for blastocyst adhesion. PLoS One. 2010;5:e13380. doi:10.1371/journal.pone.00133805.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Estrach S, Lee SA, Boulter E, Pisano S, Errante A, Tissot FS, Cailleteau L, Pons C, Ginsberg MH, Féral CC, et al. CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction. Cancer Res. 2014;74:6878–89. doi:10.1158/0008-5472.CAN-14-057974.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Fenczik CA, Sethi T, Ramos JW, Hughes PE, Ginsberg MH, et al. Complementation of dominant suppression implicates CD98 in integrin activation. Nature. 1997;390:81–5. doi:10.1038/36349390.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Feral CC, Nishiya N, Fenczik CA, Stuhlmann H, Slepak M, Ginsberg MH, et al. CD98hc (SLC3A2) mediates integrin signaling. Proc Natl Acad Sci U S A. 2005;102:355–60. doi:10.1073/pnas.0404852102102.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Féral CC, Zijlstra A, Tkachenko E, Prager G, Gardel ML, Slepak M, Ginsberg MH, et al. CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. J Cell Biol. 2007;178:701–11. doi:10.1083/jcb.200705090178.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fort J, de la Ballina LR, Burghardt HE, Ferrer-Costa C, Turnay J, Ferrer-Orta C, Usón I, Zorzano A, Fernández-Recio J, Orozco M, Lizarbe MA, Fita I, Palacín M, et al. The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane. J Biol Chem. 2007;282:31444–52. doi:10.1074/jbc.M704524200282.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fotiadis D, Kanai Y, Palacín M, et al. The SLC3 and SLC7 families of amino acid transporters. Mol Asp Med. 2013;34:139–58. doi:10.1016/j.mam.2012.10.00734.CrossRefGoogle Scholar
  19. Ip H, Sethi T, et al. CD98 signals controlling tumorigenesis. Int J Biochem Cell Biol. 2016;81:148–50. doi:10.1016/j.biocel.2016.11.00581.CrossRefPubMedPubMedCentralGoogle Scholar
  20. de la Ballina LR, Cano-Crespo S, González-Muñoz E, Bial S, Estrach S, Cailleteau L, Tissot F, Daniel H, Zorzano A, Ginsberg MH, Palacín M, Féral CC, et al. Amino acid transport associated to cluster of differentiation 98 heavy chain (CD98hc) is at the cross-road of oxidative stress and amino acid availability. J Biol Chem. 2016;291:9700–11. doi:10.1074/jbc.M115.704254291.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lemaître G, Stella A, Feteira J, Baldeschi C, Vaigot P, Martin MT, Monsarrat B, Waksman G, et al. CD98hc (SLC3A2) is a key regulator of keratinocyte adhesion. J Dermatol Sci. 2011;61:169–79. doi:10.1016/j.jdermsci.2010.12.00761.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Liao Z, Cantor JM, et al. Endothelial cells require CD98 for efficient angiogenesis-brief report. Arterioscler Thromb Vasc Biol. 2016;36:2163–6. doi:10.1161/ATVBAHA.116.30833536.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Liu X, Charrier L, Gewirtz A, Sitaraman S, Merlin D, et al. CD98 and intracellular adhesion molecule I regulate the activity of amino acid transporter LAT-2 in polarized intestinal epithelia. J Biol Chem. 2003;278:23672–7. doi:10.1074/jbc.M302777200278.CrossRefPubMedPubMedCentralGoogle Scholar
  24. McCracken AN, Edinger AL, et al. Nutrient transporters: the Achilles’ heel of anabolism. Trends Endocrinol Metab. 2013;24:200–8. doi:10.1016/j.tem.2013.01.00224.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D, et al. LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun. 2015;6:7250. doi:10.1038/ncomms82506.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Nguyen HT, Dalmasso G, Torkvist L, Halfvarson J, Yan Y, Laroui H, Shmerling D, Tallone T, D’Amato M, Sitaraman SV, Merlin D, et al. CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice. J Clin Invest. 2011;121:1733–47. doi:10.1172/JCI44631121.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136:521–34. doi:10.1016/j.cell.2008.11.044136.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Palacín M, Errasti-Murugarren E, Rosell A, et al. Heteromeric amino acid transporters. In search of the molecular bases of transport cycle mechanisms. Biochem Soc Trans. 2016;44:745–52. doi:10.1042/BST2015029444.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Reig N, Chillarón J, Bartoccioni P, Fernández E, Bendahan A, Zorzano A, Kanner B, Palacín M, Bertran J, et al. The light subunit of system b(o,+) is fully functional in the absence of the heavy subunit. EMBO J. 2002;21:4906–14.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Rosell A, Meury M, Álvarez-Marimon E, Costa M, Pérez-Cano L, Zorzano A, Fernández-Recio J, Palacín M, Fotiadis D, et al. Structural bases for the interaction and stabilization of the human amino acid transporter LAT2 with its ancillary protein 4F2hc. Proc Natl Acad Sci U S A. 2014;111:2966–71. doi:10.1073/pnas.1323779111111.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Safory H, Neame S, Shulman Y, Zubedat S, Radzishevsky I, Rosenberg D, Sason H, Engelender S, Avital A, Hülsmann S, Schiller J, Wolosker H, et al. The alanine-serine-cysteine-1 (Asc-1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission. EMBO Rep. 2015;16:590–8. doi:10.15252/embr.20143956116.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Takesono A, Moger J, Farooq S, Cartwright E, Dawid IB, Wilson SW, Kudoh T. Solute carrier family 3 member 2 (Slc3a2) controls yolk syncytial layer (YSL) formation by regulating microtubule networks in the zebrafish embryo. Proc Natl Acad Sci U S A. 2012;109(9):3371–6. doi:10.1073/pnas.1200642109.CrossRefGoogle Scholar
  33. Tărlungeanu DC, Deliu E, Dotter CP, Kara M, Janiesch PC, Scalise M, Galluccio M, Tesulov M, Morelli E, Sonmez FM, Bilguvar K, Ohgaki R, Kanai Y, Johansen A, Esharif S, Ben-Omran T, Topcu M, Schlessinger A, Indiveri C, Duncan KE, Caglayan AO, Gunel M, Gleeson JG, Novarino G, et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 2016;167:1481–94.e18. doi:10.1016/j.cell.2016.11.013167.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Torrents D, Mykkänen J, Pineda M, Feliubadaló L, Estévez R, de Cid R, Sanjurjo P, Zorzano A, Nunes V, Huoponen K, Reinikainen A, Simell O, Savontaus ML, Aula P, Palacín M, et al. Identification of SLC7A7, encoding y + LAT-1, as the lysinuric protein intolerance gene. Nat Genet. 1999;21:293–6. doi:10.1038/680921.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Tsumura H, Suzuki N, Saito H, Kawano M, Otake S, Kozuka Y, Komada H, Tsurudome M, Ito Y, et al. The targeted disruption of the CD98 gene results in embryonic lethality. Biochem Biophys Res Commun. 2003;308:847–51.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Veettil MV, Sadagopan S, Sharma-Walia N, Wang FZ, Raghu H, Varga L, Chandran B, et al. Kaposi’s sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol. 2008;82:12126–44. doi:10.1128/JVI.01146-0882.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Xu D, Hemler ME, et al. Metabolic activation-related CD147-CD98 complex. Mol Cell Proteomics. 2005;4:1061–71. doi:10.1074/mcp.M400207-MCP2004.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Yan Y, Vasudevan S, Nguyen HT, Merlin D, et al. Intestinal epithelial CD98: an oligomeric and multifunctional protein. Biochim Biophys Acta. 2008;1780:1087–92. doi:10.1016/j.bbagen.2008.06.0071780.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Zent R, Fenczik CA, Calderwood DA, Liu S, Dellos M, Ginsberg MH, et al. Class-and splice variant-specific association of CD98 with integrin beta cytoplasmic domains. J Biol Chem. 2000;275:5059.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute for Research in Biomedicine (IRB Barcelona)The Barcelona Institute of Science and TechnologyBarcelonaSpain
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of BarcelonaBarcelonaSpain
  3. 3.Department of Molecular Medicine, Institute of Basic Medical ScienceUniversity of OsloOsloNorway
  4. 4.Université Côte d’Azur, INSERM, CNRS, IRCANNiceFrance
  5. 5.Spanish Biomedical Research Network in Rare Diseases (CIBERER CB06/07/0100)BarcelonaSpain