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Alternative titles; symbolsNFATXNFAT4HGNC Approved Gene Symbol: NFATC3Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:68,085,369-68,229,258 (f...

Alternative titles; symbols

  • NFAT4

HGNC Approved Gene Symbol: NFATC3

Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:68,085,369-68,229,258 (from NCBI)

▼ 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 and NFATC4 (602699), 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 (see 165160). 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.

By PCR using degenerate primers designed from the purified protein, followed by screening a Jurkat human T-cell cDNA library, Masuda et al. (1995) cloned NFATC3, which they called NFATx. The deduced 1,075-amino acid protein has a calculated molecular mass of about 116 kD. NFATC3 contains an N-terminal and proline-rich SP box motif that is repeated 3 times, and a central Rel homology domain, which includes a nuclear localization signal. Northern blot analysis detected a 7.0-kb transcript expressed at a high level in thymus and more weakly in leukocytes. Prolonged exposure revealed weak NFATC3 expression in testis, ovary, spleen, muscle, kidney, prostate, small intestine, colon, placenta, lung, and liver. No expression was detected in heart, brain, or pancreas. Purified Jurkat T-cell NFATC3 had an apparent molecular mass of 120 kD.

▼ Gene Function
The activation of NFAT proteins is controlled by calcineurin (see 114105), the calmodulin-dependent phosphatase. Aramburu et al. (1998) identified a short conserved sequence in the NFATC3 protein (residues 105-117) 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.

Masuda et al. (1995) demonstrated that NFATC3 can bind the NFAT-binding site from the interleukin-2 (147680) promoter when combined with purified AP1 or with recombinant c-Fos (164810) and c-Jun (165160). Furthermore, NFATC3 activated transcription of the interleukin-2 promoter in COS-7 cells when stimulated with phorbol ester and calcium ionophore.

Helicobacter pylori CagA-positive strains inject CagA into host cells, where the protein is tyrosine phosphorylated. Tyrosine-phosphorylated CagA binds to and deregulates the phosphatase activity of SHP2 (PTPN11; 176876), causing an elongated cell shape termed the 'hummingbird phenotype.' Using AGS gastric epithelial cells exposed to H. pylori CagA and microarray analysis, Yokoyama et al. (2005) showed that CagA activated NFAT proteins, principally NFATC3, and NFAT-dependent proteins, such as p21 (CDKN1A; 116899). Flow cytometric, immunofluorescence microscopy, and EMSA analyses demonstrated that CagA expression caused translocation of NFATC3 from the cytoplasm to the nucleus in a phospholipase C-gamma (see 600220)- and calcineurin-dependent manner. Exposure of AGS cells to another H. pylori virulence factor, the VacA vacuolating toxin, counteracted CagA-induced NFAT activation without preventing induction of the hummingbird phenotype. Yokoyama et al. (2005) suggested that deregulation of NFAT, either positively or negatively, may contribute to cellular dysfunctions that underlie diverged clinical manifestations caused by H. pylori infection.

Saadat et al. (2007) showed that H. pylori CagA specifically interacts with PAR1/MARK kinase (see MARK2, 600526), which has an essential role in epithelial cell polarity. Because of the multimeric nature of PAR1, PAR1 also promoted CagA multimerization, which stabilized the CagA-SHP2 interaction. Furthermore, induction of the hummingbird phenotype by CagA-activated SHP2 required simultaneous inhibition of PAR1 kinase activity by CagA. Thus, Saadat et al. (2007) concluded that the CagA-PAR1 interaction not only elicits the junctional and polarity defects but also promotes the morphogenetic activity of CagA.

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 (602699). Purification of Nfat protein 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.

Lin et al. (2009) found that the hypertrophic response of rat cardiomyocytes to isoproterenol or aldosterone required a pathway that included calcineurin, Nfatc3, microRNA-23a (MIR23A; 607962), and Murf1 (RNF28; 606131). Nfatc3 directly upregulated expression of Mir23a, and elevated Mir23a levels inhibited Murf1 mRNA translation by binding to the 3-prime UTR of the Murf1 transcript. Knockdown of any of these components abrogated the hypertrophic response of cardiomyocytes to aldosterone or isoproterenol.

Calabria et al. (2009) showed that all 4 NFAT family members, including Nfatc3, 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.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the NFATC3 gene to chromosome 16 (stST42737).

By FISH, Masuda et al. (1995) mapped the NFATC3 gene to chromosome 16q21-q22.

▼ 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.

Rengarajan et al. (2002) generated Nfatc2 and Nfatc3 double-knockout (DKO) mice. They found that Nfatc2 and Nfatc3 are critical in the determination of the fate of precursor T helper (Th) cells. DKO T cells intrinsically differentiated into Th2 cytokine-secreting cells, even in the absence of IL4 (147780). Treatment of DKOs with IL12 (161561) and anti-IL4, however, enabled the cells to become gamma-interferon (IFNG; 147570)-secreting Th1 lymphocytes. In addition, the cells from the DKO mice were hyperresponsive to T-cell receptor (TCR; see 186880)-mediated activation and did not require the engagement of the accessory receptor, CD28 (186760), for proliferation.

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.

Gallo et al. (2007) demonstrated that mice deficient in Cnb1 (601302) or Nfatc2/c3 lacked a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and failed to undergo positive selection. This defect could be partially rescued with constitutively active Raf (164760), indicating that calcineurin controls MAPK signaling. Analysis of mice deficient in both Bim (603827) and Cnb1 revealed that calcineurin-induced ERK sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). Gallo et al. (2007) concluded that early calcineurin/NFAT signaling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection.

Ma et al. (2014) found that overexpression of the Toxoplasma gondii Gra6 protein in mice resulted in Camlg (601118)-dependent activation of Nat4. T. gondii parasites lacking Gra6 failed to exhibit full virulence in local infection, and treatment of wildtype mice with an Nfat inhibitor also mitigated parasite virulence. Mice lacking Nfat4 displayed prolonged survival, decreased recruitment of Cd11b (ITGAM; 120980)-positive/Ly6g-positive cells to the infection site, and impaired expression of chemokines such as Cxcl2 (139110) and Ccl2 (158105). Ma et al. (2014) concluded that Gra6-dependent NFAT4 activation is required for manipulation of host immune responses and maximal parasite virulence.

Tags: 16q22.1