Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Rachel Y. Ames
  • Rut Valdor
  • Brian T. Abe
  • Fernando MacianEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_141


 NFATc1 (Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1; NFAT2; NFATc, NFAT cytoplasmic);  NFATc2 (Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2; NFAT1; NFATp, NFAT preexisting);  NFATc3 (Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3; NFAT4; NFATx);  NFATc4 (Nuclear factor of activated T-cells cytoplasmic calcineurin dependent 4, NFAT3);  NFAT5 (Nuclear factor of activated T-cells 5; TonEBP, Tonicity-responsive enhancer binding protein; OREBP, Osmotic response element-binding protein)

Historical Background

The gene encoding for the first nuclear factor of activated T cells (NFAT) protein was cloned more than 20 years ago and termed NFATp, as it was shown to be “preexistent” in the cytosol of resting T cells. In activated T cells, NFATp interacted with the transcription factors Fos and Jun in the nucleus to induce the expression of interleukin (IL-) 2 (Jain et al. 1993). Soon after, new members of the...

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


  1. Aramburu J, Drews-Elger K, Estrada-Gelonch A, Minguillon J, Morancho B, Santiago V, et al. Regulation of the hypertonic stress response and other cellular functions by the Rel-like transcription factor NFAT5. Biochem Pharmacol. 2006;72:1597–604.  https://doi.org/10.1016/j.bcp.2006.07.002.CrossRefPubMedGoogle Scholar
  2. Baine I, Abe BT, Macian F. Regulation of T-cell tolerance by calcium/NFAT signaling. Immunol Rev. 2009;231:225–40.  https://doi.org/10.1111/j.1600-065X.2009.00817.x.CrossRefPubMedGoogle Scholar
  3. Chen L, Glover JN, Hogan PG, Rao A, Harrison SC. Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature. 1998;392:42–8.  https://doi.org/10.1038/32100.CrossRefPubMedGoogle Scholar
  4. Fric J, Zelante T, Wong AY, Mertes A, Yu HB, Ricciardi-Castagnoli P. NFAT control of innate immunity. Blood. 2012;120:1380–9.  https://doi.org/10.1182/blood-2012-02-404475.CrossRefPubMedGoogle Scholar
  5. Gallo EM, Winslow MM, Cante-Barrett K, Radermacher AN, Ho L, McGinnis L, et al. Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature. 2007;450:731–5.  https://doi.org/10.1038/nature06305.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17:2205–32.  https://doi.org/10.1101/gad.1102703.CrossRefPubMedCentralPubMedGoogle Scholar
  7. Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993;365:352–5.  https://doi.org/10.1038/365352a0.CrossRefPubMedGoogle Scholar
  8. Li X, Zhu L, Yang A, Lin J, Tang F, Jin S, et al. Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos. Cell Stem Cell. 2011;8:46–58.  https://doi.org/10.1016/j.stem.2010.11.027.CrossRefPubMedGoogle Scholar
  9. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol. 2011;12:1063–70.  https://doi.org/10.1038/ni.2113.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Lopez-Rodriguez C, Aramburu J, Jin L, Rakeman AS, Michino M, Rao A. Bridging the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. Immunity. 2001;15:47–58.CrossRefPubMedGoogle Scholar
  11. Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005;5:472–84.  https://doi.org/10.1038/nri1632.CrossRefPubMedGoogle Scholar
  12. Macian F, Lopez-Rodriguez C, Rao A. Partners in transcription: NFAT and AP-1. Oncogene. 2001;20:2476–89.  https://doi.org/10.1038/sj.onc.1204386.CrossRefPubMedGoogle Scholar
  13. Mancini M, Toker A. NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer. 2009;9:810–20.  https://doi.org/10.1038/nrc2735.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Martinez GJ, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, et al. Cutting edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection. J Immunol. 2016;196:2015–9.  https://doi.org/10.4049/jimmunol.1501841.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Muller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010;10:645–56.  https://doi.org/10.1038/nri2818.CrossRefPubMedGoogle Scholar
  16. Oh-hora M, Rao A. Calcium signaling in lymphocytes. Curr Opin Immunol. 2008;20:250–8.  https://doi.org/10.1016/j.coi.2008.04.004.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Patra AK, Avots A, Zahedi RP, Schuler T, Sickmann A, Bommhardt U, et al. An alternative NFAT-activation pathway mediated by IL-7 is critical for early thymocyte development. Nat Immunol. 2013;14:127–35.  https://doi.org/10.1038/ni.2507.CrossRefPubMedGoogle Scholar
  18. Serfling E, Chuvpilo S, Liu J, Hofer T, Palmetshofer A. NFATc1 autoregulation: a crucial step for cell-fate determination. Trends Immunol. 2006;27:461–9.  https://doi.org/10.1016/j.it.2006.08.005.CrossRefPubMedGoogle Scholar
  19. Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z, et al. Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci USA. 2011;108:11381–6.  https://doi.org/10.1073/pnas.1019711108.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Sitara DA, Aliprantis O. Transcriptional regulation of bone and joint remodeling by NFAT. Immunol Rev. 2010;233:286–300.  https://doi.org/10.1111/j.0105-2896.2009.00849.x.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006;126:375–87.  https://doi.org/10.1016/j.cell.2006.05.042.CrossRefPubMedGoogle Scholar
  22. Wu H, Peisley A, Graef IA, Crabtree GR. NFAT signaling and the invention of vertebrates. Trends Cell Biol. 2007;17:251–60.  https://doi.org/10.1016/j.tcb.2007.04.006.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Rachel Y. Ames
    • 1
  • Rut Valdor
    • 2
  • Brian T. Abe
    • 3
  • Fernando Macian
    • 1
    Email author
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Human Anatomy and PsychobiologyUniversity of Murcia School of Medicine and Instituto Murciano de Investigación BiosanitariaMurciaSpain
  3. 3.Scripps Translational Science InstituteLa JollaUSA