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Gene Review

NFATC2  -  nuclear factor of activated T-cells,...

Homo sapiens

Synonyms: NF-ATP, NF-ATc2, NF-ATp, NFAT pre-existing subunit, NFAT1, ...
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Disease relevance of NFATC2


High impact information on NFATC2

  • Recent findings in B lymphocytes have clearly illustrated that these external inputs affect the magnitude and duration of the intracellular calcium response, which in turn contributes to differential triggering of the transcriptional regulators NF kappa B, JNK, NFAT, and ERK [5].
  • NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells [6].
  • As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much attention [6].
  • The activity of NFAT proteins is tightly regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a primary target for inhibition by cyclosporin A and FK506 [6].
  • NFAT proteins, which are expressed in most immune-system cells, play a pivotal role in the transcription of cytokine genes and other genes critical for the immune response [6].

Chemical compound and disease context of NFATC2


Biological context of NFATC2

  • The nuclear factor of the activated T cell (NFAT) family of transcription factors regulates cytokine gene expression by binding to the promoter/enhancer regions of antigen-responsive genes, usually in cooperation with heterologous DNA-binding partners [11].
  • The other protein, NF-ATp, is highly homologous to NF-ATc over a limited domain which shows similarity to the Dorsal/Rel family, but has a wider tissue distribution [12].
  • We have defined the mechanisms of transactivation by NFAT1 [13].
  • The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family [13].
  • These results implicate NFAT as an important mediator of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-protein interaction with other transcription factors [14].

Anatomical context of NFATC2

  • Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system [15].
  • NK cell NFAT is present in the cytosol of nonstimulated cells, migrates to the nucleus upon stimulation, and can associate with AP-1 [16].
  • Stimulation of NK cells with CD16 ligands induces NFAT-like DNA binding activity in the nuclear extracts from these cells, as detected in electrophoretic mobility shift assays [16].
  • In A20 B cells, the TNF-alpha gene is not regulated by NFATp bound to the kappa 3 element [17].
  • DNA-binding of silencer and activator from T-helper, and NFAT-1 from Jurkat cells, requires the same three G residues, but cross-linking analyses show differences in their constituent subunits [18].

Associations of NFATC2 with chemical compounds

  • Furthermore, pharmacological studies demonstrate that the drug cyclosporin A inhibits both NFAT activation and IL-2 expression [19].
  • In DNA binding assays, both PMA plus anti-CD28 and PMA plus ionomycin resulted in nuclear NFAT [20].
  • Vav also did not stimulate detectable Ca(2+) mobilization and nuclear translocation of NFATc or NFATp [21].
  • Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1 [22].
  • Furthermore, mutation or deletion of NFAT binding sites in the human COX-2 promoter greatly diminished its induction by phorbol 12-myristate 13-acetate/calcium ionophore A23187 [23].

Physical interactions of NFATC2

  • It has been shown that nuclear factor of activated T cells (NFAT) interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism of activation of MEF2D by calcineurin [14].
  • Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin alpha6beta4 expressing cells [24].
  • Previously, we have shown that NFATc.beta, an isoform of NFATc, is different from NFATp in both DNA binding and transactivation of the TNF-alpha promoter [25].
  • As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter [26].
  • Competition with an AP-1 motif or with anti-Jun and anti-Fos antibodies abolished binding to the NFAT motif in both T and B cells, indicating that Jun and Fos are critical for NFAT complex formation in both cell types [27].

Enzymatic interactions of NFATC2

  • We show here that the peptidyl prolyl cis-trans isomerase Pin1 interacts specifically with the phosphorylated form of NFAT [28].

Regulatory relationships of NFATC2


Other interactions of NFATC2

  • We report here that NFATp synergizes with MEF2D to recruit the coactivator p300 for the transcription of Nur77 [14].
  • Comparison to other NFAT structures, including NFAT5 and the NFAT1-Fos-Jun-ARRE2 complex, reveals that NFAT1 adopts different conformations and its protein surfaces mediate distinct protein-protein interactions in the context of different DNA sites [1].
  • Properties of transcription factors regulating interleukin-2 gene transcription through the NFAT binding site in untreated or drug-treated naive and memory T-helper cells [18].
  • Electromobility shift assays showed that NFAT1 and activator protein-1 are both translocated to the nucleus following bpV treatment [35].
  • The NFAT-dependent promoters from the IL-2 and TNF-alpha genes were also more potently activated by PMA/Iono in J45.01 cells [33].

Analytical, diagnostic and therapeutic context of NFATC2


  1. Structure of NFAT1 bound as a dimer to the HIV-1 LTR kappa B element. Giffin, M.J., Stroud, J.C., Bates, D.L., von Koenig, K.D., Hardin, J., Chen, L. Nat. Struct. Biol. (2003) [Pubmed]
  2. Equivalent functional nuclear factor of activated T cell 1 mRNA and protein expression in cord blood and adult T cells. O'Neill, R.M., Reen, D.J. Transplantation (2003) [Pubmed]
  3. Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc. Wolfe, S.A., Zhou, P., Dötsch, V., Chen, L., You, A., Ho, S.N., Crabtree, G.R., Wagner, G., Verdine, G.L. Nature (1997) [Pubmed]
  4. Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A. Al-Daraji, W.I., Grant, K.R., Ryan, K., Saxton, A., Reynolds, N.J. J. Invest. Dermatol. (2002) [Pubmed]
  5. Positive versus negative signaling by lymphocyte antigen receptors. Healy, J.I., Goodnow, C.C. Annu. Rev. Immunol. (1998) [Pubmed]
  6. Transcription factors of the NFAT family: regulation and function. Rao, A., Luo, C., Hogan, P.G. Annu. Rev. Immunol. (1997) [Pubmed]
  7. Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat. Li, C., Lai, C.F., Sigman, D.S., Gaynor, R.B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Holzmann, K., Kohlhammer, H., Schwaenen, C., Wessendorf, S., Kestler, H.A., Schwoerer, A., Rau, B., Radlwimmer, B., Döhner, H., Lichter, P., Gress, T., Bentz, M. Cancer Res. (2004) [Pubmed]
  9. Reciprocal regulation of the nuclear factor of activated T cells and HIV-1. Pessler, F., Cron, R.Q. Genes Immun. (2004) [Pubmed]
  10. NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Pu, W.T., Ma, Q., Izumo, S. Circ. Res. (2003) [Pubmed]
  11. Solution structure of the core NFATC1/DNA complex. Zhou, P., Sun, L.J., Dötsch, V., Wagner, G., Verdine, G.L. Cell (1998) [Pubmed]
  12. NF-AT components define a family of transcription factors targeted in T-cell activation. Northrop, J.P., Ho, S.N., Chen, L., Thomas, D.J., Timmerman, L.A., Nolan, G.P., Admon, A., Crabtree, G.R. Nature (1994) [Pubmed]
  13. Mechanisms of transactivation by nuclear factor of activated T cells-1. Luo, C., Burgeon, E., Rao, A. J. Exp. Med. (1996) [Pubmed]
  14. Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. Youn, H.D., Chatila, T.A., Liu, J.O. EMBO J. (2000) [Pubmed]
  15. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. Rengarajan, J., Mowen, K.A., McBride, K.D., Smith, E.D., Singh, H., Glimcher, L.H. J. Exp. Med. (2002) [Pubmed]
  16. Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding. Aramburu, J., Azzoni, L., Rao, A., Perussia, B. J. Exp. Med. (1995) [Pubmed]
  17. Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Tsai, E.Y., Yie, J., Thanos, D., Goldfeld, A.E. Mol. Cell. Biol. (1996) [Pubmed]
  18. Properties of transcription factors regulating interleukin-2 gene transcription through the NFAT binding site in untreated or drug-treated naive and memory T-helper cells. Mouzaki, A., Rungger, D. Blood (1994) [Pubmed]
  19. Requirement for transcription factor NFAT in interleukin-2 expression. Chow, C.W., Rincón, M., Davis, R.J. Mol. Cell. Biol. (1999) [Pubmed]
  20. Expression of NFAT-family proteins in normal human T cells. Lyakh, L., Ghosh, P., Rice, N.R. Mol. Cell. Biol. (1997) [Pubmed]
  21. Vav-Rac1-mediated activation of the c-Jun N-terminal kinase/c-Jun/AP-1 pathway plays a major role in stimulation of the distal NFAT site in the interleukin-2 gene promoter. Kaminuma, O., Deckert, M., Elly, C., Liu, Y.C., Altman, A. Mol. Cell. Biol. (2001) [Pubmed]
  22. Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells. Martínez-Martínez, S., Gómez del Arco, P., Armesilla, A.L., Aramburu, J., Luo, C., Rao, A., Redondo, J.M. Mol. Cell. Biol. (1997) [Pubmed]
  23. Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. Duque, J., Fresno, M., Iñiguez, M.A. J. Biol. Chem. (2005) [Pubmed]
  24. Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Chen, M., O'Connor, K.L. Oncogene (2005) [Pubmed]
  25. Molecular mechanism of NFAT family proteins for differential regulation of the IL-2 and TNF-alpha promoters. Oum, J.H., Han, J., Myung, H., Hleb, M., Sharma, S., Park, J. Mol. Cells (2002) [Pubmed]
  26. T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells. Cron, R.Q., Bort, S.J., Wang, Y., Brunvand, M.W., Lewis, D.B. J. Immunol. (1999) [Pubmed]
  27. Comparative analysis of NFAT (nuclear factor of activated T cells) complex in human T and B lymphocytes. Yaseen, N.R., Maizel, A.L., Wang, F., Sharma, S. J. Biol. Chem. (1993) [Pubmed]
  28. Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1. Liu, W., Youn, H.D., Zhou, X.Z., Lu, K.P., Liu, J.O. FEBS Lett. (2001) [Pubmed]
  29. Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity. San-Antonio, B., Iñiguez, M.A., Fresno, M. J. Biol. Chem. (2002) [Pubmed]
  30. Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation. Guo, S., Lopez-Ilasaca, M., Dzau, V.J. J. Biol. Chem. (2005) [Pubmed]
  31. Selective expression of nuclear factor of activated T cells 2/c1 in human basophils: evidence for involvement in IgE-mediated IL-4 generation. Schroeder, J.T., Miura, K., Kim, H.H., Sin, A., Cianferoni, A., Casolaro, V. J. Allergy Clin. Immunol. (2002) [Pubmed]
  32. Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Decker, E.L., Nehmann, N., Kampen, E., Eibel, H., Zipfel, P.F., Skerka, C. Nucleic Acids Res. (2003) [Pubmed]
  33. Negative regulation of the NFAT1 factor by CD45: implication in HIV-1 long terminal repeat activation. Barbeau, B., Robichaud, G.A., Fortin, J.F., Tremblay, M.J. J. Immunol. (2001) [Pubmed]
  34. Differential contribution of NFATc2 and NFATc1 to TNF-alpha gene expression in T cells. Kaminuma, O., Kitamura, F., Kitamura, N., Hiroi, T., Miyoshi, H., Miyawaki, A., Miyatake, S. J. Immunol. (2008) [Pubmed]
  35. Treatment of human T cells with bisperoxovanadium phosphotyrosyl phosphatase inhibitors leads to activation of cyclooxygenase-2 gene. Barat, C., Tremblay, M.J. J. Biol. Chem. (2003) [Pubmed]
  36. Human eosinophils constitutively express nuclear factor of activated T cells p and c. Seminario, M.C., Guo, J., Bochner, B.S., Beck, L.A., Georas, S.N. J. Allergy Clin. Immunol. (2001) [Pubmed]
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