Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 602699

NUCLEAR FACTOR OF ACTIVATED T CELLS, CYTOPLASMIC, CALCINEURIN-DEPENDENT 4; NFATC4

Alternative titles; symbols

NFAT3

HGNC Approved Gene Symbol: NFATC4

Cytogenetic location: 14q12 Genomic coordinates (GRCh38) : 14:24,366,911-24,379,604 (from NCBI)

TEXT

Description

NFAT (nuclear factors of activated T cells) proteins are a family of transcription factors originally identified as mediators of activation of cytokine genes in response to antigenic stimulation of T cells. NFAT proteins also play varied roles in cells outside of the immune system. For a review, see Horsley and Pavlath (2002).

Cloning and Expression

Hoey et al. (1995) isolated 2 members of the NFAT gene family, NFATC3 (602698) and NFATC4, which encode proteins that are 65% identical to NFATC1 (600489) and NFATC2 (600490) within a 290-amino acid domain distantly related to the Rel domain. The 4 NFAT genes are transcribed in different sets of tissues that include many sites of expression outside the immune system. The Rel homology domain is sufficient for DNA recognition and cooperative binding interactions with AP1. Although other members of the Rel family bind DNA as dimers, NFAT proteins are monomers in solution or bound to DNA. Transfection assays indicate that each of the 4 NFAT proteins can activate the IL2 promoter in T cells.

Gene Function

The activation of NFAT proteins is controlled by calcineurin, the calmodulin-dependent phosphatase. Aramburu et al. (1998) identified a short conserved sequence in the NFATC4 protein (residues 110-122) that targets calcineurin to NFAT. Mutation of a single residue in this sequence impairs the calcineurin-mediated dephosphorylation and nuclear translocation of NFAT1. Peptides spanning the region inhibit the ability of calcineurin to bind to and dephosphorylate NFAT proteins, without affecting the phosphatase activity of calcineurin against other substrates. When expressed intracellularly, a corresponding peptide inhibits NFAT dephosphorylation, nuclear translocation, and NFAT-mediated expression in response to stimulation. Thus, disruption of the enzyme-substrate docking interaction that directs calcineurin to NFAT can effectively block NFAT-dependent functions.

Kao et al. (2009) found that mice lacking calcineurin B1 (CNB1; 601302) in the neural crest had defects in Schwann cell differentiation and myelination. Neuregulin (NRG1; 142445) addition to Schwann cell precursors initiated an increase in cytoplasmic calcium ion, which activated calcineurin and the downstream transcription factors Nfatc3 and Nfatc4. Purification of Nfat complexes showed that Sox10 (602229) is an Nfat nuclear partner and synergizes with Nfatc4 to activate Krox20 (129010), which regulates genes necessary for myelination. Kao et al. (2009) concluded that calcineurin and NFAT are essential for neuregulin and ErbB (see 131550) signaling, neural crest diversification, and differentiation of Schwann cells.

Calabria et al. (2009) showed that all 4 NFAT family members, including Nfatc4, were expressed in rat skeletal muscle. The NFAT proteins shuttled between nucleus and cytoplasm in response to plasma membrane electrical activity, and different combinations of NFAT proteins controlled specific transcription in slow or fast muscle fibers.

Estrogen receptor-alpha (ERA, or ESR1; 133430)-positive breast cancer cells are less invasive than ERA-negative breast cancer cells. Fougere et al. (2010) found that ERA-positive breast cancer cells had upregulated expression of NFAT3 and downregulated expression of LCN2 (600181) compared with ERA-negative breast cancer cells. Overexpression and knockdown studies suggested that NFAT3 cooperated with ERA in downregulation of LCN2, although indirectly, and downregulated LCN2 expression correlated with reduced invasiveness and metastasis.

Mapping

Stumpf (2024) mapped the NFATC4 gene to chromosome 14q12 based on an alignment of the NFATC4 sequence (GenBank BC053855) with the genomic sequence (GRCh38).

Animal Model

Graef et al. (2001) found that mice with disruptions of both the Nfatc4 and Nfatc3 genes died around embryonic day 11 (E11) with generalized defects in vessel assembly as well as excessive and disorganized growth of vessels into the neural tube and somites. Since calcineurin was thought to control nuclear localization of NFATC proteins, the authors introduced a mutation into the calcineurin B gene (601302) that prevented phosphatase activation by calcium signals. These calcineurin B mutant mice exhibited vascular developmental abnormalities similar to those of the Nfatc3/Nfatc4 null mice. Graef et al. (2001) showed that calcineurin function was transiently required between E7.5 and E8.5. They concluded that early calcineurin/NFAT signaling initiates the later cross-talk between vessels and surrounding tissues that pattern the vasculature.

Graef et al. (2003) found that mice deficient in calcineurin (see 114105)-NFAT signaling had dramatic defects in axonal outgrowth, yet they had little or no defect in neuronal differentiation or survival. In vitro, sensory and commissural neurons lacking calcineurin function or Nfatc2, Nfatc3, and Nfatc4 were unable to respond to neurotrophins (see 162010) or netrin-1 (601614) with efficient axonal outgrowth. Neurotrophins and netrins stimulated calcineurin-dependent nuclear localization of Nfatc4 and activation of NFAT-mediated gene transcription in cultured primary neurons. These data indicated that the ability of these embryonic axons to respond to growth factors with rapid outgrowth requires activation of calcineurin/NFAT signaling by these factors. The authors proposed that the precise parsing of signals for elongation, turning, and survival could allow independent control of these processes during development.

Bushdid et al. (2003) examined embryonic heart development in mice doubly null for Nfatc3 and Nfatc4. The mice demonstrated embryonic lethality after E10.5, with thin ventricles, pericardial effusion, and reduced ventricular myocyte proliferation. Cardiac mitochondria were swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis were not evident. Cardiomyocyte enzymatic activity of complexes II and IV of the respiratory chain and mitochondrial oxidative activity were reduced. Restoration of NFAT activity prolonged embryonic viability to E12 and preserved ventricular myocyte proliferation, compact zone density, and trabecular formation; cardiac mitochondrial ultrastructure and complex II enzyme activity were also maintained. Bushdid et al. (2003) concluded that their data supported the hypothesis that loss of NFAT activity in the heart results in a deficiency in the mitochondrial energy metabolism required for cardiac morphogenesis and function.

Chang et al. (2004) showed that initiation of heart valve morphogenesis in mice required Cnb1, Nfatc2, Nfatc3, and Nfatc4 to repress Vegf expression in the myocardium underlying the site of prospective valve formation. Repression of Vegf at mouse E9 was essential for endocardial cells to transform into mesenchymal cells. Later, at E11, Cnb1/Nfatc1 signaling was required in the endocardium, adjacent to the earlier myocardial site of NFAT action, to direct valvular elongation and refinement. Chang et al. (2004) concluded that NFAT signaling functions sequentially from myocardium to endocardium within a valvular morphogenetic field to initiate and perpetuate embryonic valve formation. They found that this mechanism also operates in zebrafish, indicating a conserved role for calcineurin/NFAT signaling in vertebrate heart valve morphogenesis.

REFERENCES

  1. Aramburu, J., Garcia-Cozar, F., Raghavan, A., Okamura, H., Rao, A., Hogan, P. G.Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Molec. Cell 1: 627-637, 1998. [PubMed: 9660947] [Full Text: https://doi.org/10.1016/s1097-2765(00)80063-5\]
  2. Bushdid, P. B., Osinska, H., Waclaw, R. R., Molkentin, J. D., Yutzey, K. E.NFATc3 and NFATc4 are required for cardiac development and mitochondrial function. Circ. Res. 92: 1305-1313, 2003. [PubMed: 12750314] [Full Text: https://doi.org/10.1161/01.RES.0000077045.84609.9F\]
  3. Calabria, E., Ciciliot, S., Moretti, I., Garcia, M., Picard, A., Dyar, K. A., Pallafacchina, G., Tothova, J., Schiaffino, S., Murgia, M.NFAT isoforms control activity-dependent muscle fiber type specification. Proc. Nat. Acad. Sci. 106: 13335-13340, 2009. [PubMed: 19633193] [Full Text: https://doi.org/10.1073/pnas.0812911106\]
  4. Chang, C.-P., Neilson, J. R., Bayle, J. H., Gestwicki, J. E., Kuo, A., Stankunas, K., Graef, I. A., Crabtree, G. R.A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118: 649-663, 2004. [PubMed: 15339668] [Full Text: https://doi.org/10.1016/j.cell.2004.08.010\]
  5. Fougere, M., Gaudineau, B., Barbier, J., Guaddachi, F., Feugeas, J.-P., Auboeuf, D., Jauliac, S.NFAT3 transcription factor inhibits breast cancer cell motility by targeting the lipocalin 2 gene. Oncogene 29: 2292-2301, 2010. [PubMed: 20101218] [Full Text: https://doi.org/10.1038/onc.2009.499\]
  6. Graef, I. A., Chen, F., Chen, L., Kuo, A., Crabtree, G. R.Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105: 863-875, 2001. [PubMed: 11439183] [Full Text: https://doi.org/10.1016/s0092-8674(01)00396-8\]
  7. Graef, I. A., Wang, F., Charron, F., Chen, L., Neilson, J., Tessier-Lavigne, M., Crabtree, G. R.Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113: 657-670, 2003. [PubMed: 12787506] [Full Text: https://doi.org/10.1016/s0092-8674(03)00390-8\]
  8. Hoey, T., Sun, Y. L., Williamson, K., Xu, X.Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity 2: 461-472, 1995. [PubMed: 7749981] [Full Text: https://doi.org/10.1016/1074-7613(95)90027-6\]
  9. Horsley, V., Pavlath, G. K.NFAT: ubiquitous regulator of cell differentiation and adaptation. J. Cell Biol. 156: 771-774, 2002. [PubMed: 11877454] [Full Text: https://doi.org/10.1083/jcb.200111073\]
  10. Kao, S.-C., Wu, H., Xie, J., Chang, C.-P., Ranish, J. A., Graef, I. A., Crabtree, G. R.Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation. Science 323: 651-654, 2009. [PubMed: 19179536] [Full Text: https://doi.org/10.1126/science.1166562\]
  11. Stumpf, A. M.Personal Communication. Baltimore, Md. 12/10/2024.

Contributors:

Anne M. Stumpf - updated : 12/10/2024
Bao Lige - updated : 05/15/2020
\ : 01/07/2014
Patricia A. Hartz - updated : 2/23/2012
Ada Hamosh - updated : 3/10/2009
Stylianos E. Antonarakis - updated : 9/14/2004
Marla J. F. O'Neill - updated : 3/5/2004
Stylianos E. Antonarakis - updated : 7/2/2003
Patricia A. Hartz - updated : 8/1/2002
Stylianos E. Antonarakis - updated : 7/5/2001
Stylianos E. Antonarakis - updated : 9/22/1998

Creation Date:

Stylianos E. Antonarakis : 6/9/1998

Edit History:

alopez : 12/10/2024
mgross : 05/15/2020
alopez : 01/07/2014
mgross : 3/6/2012
terry : 2/23/2012
alopez : 3/13/2009
terry : 3/10/2009
alopez : 7/31/2006
terry : 7/24/2006
mgross : 9/14/2004
mgross : 9/14/2004
tkritzer : 3/22/2004
tkritzer : 3/5/2004
mgross : 7/2/2003
carol : 8/1/2002
carol : 3/1/2002
mgross : 7/5/2001
psherman : 8/27/1999
carol : 9/22/1998
carol : 6/10/1998