Alternative titles; symbols
HGNC Approved Gene Symbol: NFATC2
Cytogenetic location: 20q13.2 Genomic coordinates (GRCh38): 20:51,386,963-51,562,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.2 | ?Joint contracture, osteochondromas, and B-cell lymphoma | 620232 | Autosomal recessive | 3 |
The NFAT (nuclear factors of activated T cells) transcription complex is a multisubunit transcription factor consisting of at least 3 DNA-binding components, including homodimers or heterodimers of FOS (164810) and JUN (165160) family proteins. NFATC2, also called NFATP, or the 'preexisting component' of NFAT, is present in the cytosolic fraction of unstimulated T cells. After T-cell activation it is found in the nucleus as a part of NFAT. For a review of NFAT proteins, see Horsley and Pavlath (2002).
Northrop et al. (1994) purified 2 proteins encoded by separate genes that represent the preexisting and cytosolic (NFATC1; 600489) components of NFAT. They showed that NFATC2 is highly homologous to NFATC1 over a limited domain which shows similarity to the Dorsal/Rel family (see 164014) but has a wider tissue distribution.
By Northern blot analysis, Masuda et al. (1995) detected expression of an NFATC2 transcript at about 8.0 kb in all tissues examined. Expression was strongest in leukocytes, spleen, and placenta, intermediate in thymus, prostate, testis, ovary, small intestine, lung, liver, muscle, kidney, and pancreas, and weakest in heart, colon, and brain.
McCaffrey et al. (1993) purified NFATP from murine T cells and isolated a cDNA clone encoding this phosphoprotein. A truncated form of NFATP, expressed as a recombinant protein in bacteria, bound specifically to the NFAT site of the murine IL2 (147680) promoter and formed a transcriptionally active complex with recombinant FOS and JUN.
Okamura et al. (2000) showed by mass spectrometry that NFAT1 is phosphorylated on 14 conserved phosphoserine residues in its regulatory domain, 13 of which are dephosphorylated upon stimulation. Dephosphorylation of all 13 residues is required to mask a nuclear export signal, cause full exposure of a nuclear localization signal, and promote transcriptional activity. An inducible phosphorylation site in the transactivation domain contributes to transcriptional activity. The data suggested that dephosphorylation promotes NFAT1 activation by increasing the probability of an active conformation, in a manner analogous to that by which depolarization increases the open probability of voltage-gated ion channels. This conformational switch paradigm may explain modification-induced functional changes in other heavily phosphorylated proteins.
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 NFATC2 protein (residues 107-119) 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.
Baksh et al. (2002) found that ectopic expression of NFATC2 inhibited the basal activity of the human CDK4 (123829) promoter. Additionally, both Calna (114105) -/- and Nfatc2 -/- mice had elevated protein levels of Cdk4, confirming a negative regulatory role for the calcineurin/NFAT pathway. This pathway may thus regulate the expression of CDK4 at the transcriptional level and control how cells reenter a resting, nonproliferative state.
Jauliac et al. (2002) found that both NFATC2 and NFAT5 (604708) were expressed in invasive human ductal breast carcinomas. Using cell lines derived from breast and colon carcinomas, they found that these NFATs promoted carcinoma invasion and that their activity correlated with expression of alpha-6 (147556)/beta-4 (147557) integrin.
NFATC2 controls myoblast fusion at a specific stage of myogenesis after the initial formation of a myotube and is necessary for further cell growth. By examining genes regulated by NFATC2 in muscle, Horsley et al. (2003) identified the cytokine IL4 (147780) as a molecular signal that controls myoblast fusion with myotubes. Mouse muscle cells lacking Il4 or the Il4 receptor alpha subunit (147781) formed normally but were reduced in size and myonuclear number. Il4 was expressed by a subset of mouse muscle cells in fusing muscle cultures and required the Il4 receptor alpha subunit on myoblasts to promote fusion and growth. These data demonstrated that following myotube formation, myotubes recruit myoblast fusion by secretion of IL4, leading to muscle growth.
Helicobacter pylori vacuolating cytotoxin VacA induces cellular vacuolation in epithelial cells. Gebert et al. (2003) found that VacA could efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest. VacA interfered with the T cell receptor/IL2 signaling pathway at the level of calcineurin. Nuclear translocation of NFAT was abrogated, resulting in downregulation of IL2 transcription. VacA partially mimicked the activity of the immunosuppressive drug FK506 by possibly inducing a local immune suppression, explaining the extraordinary chronicity of H. pylori infections.
Ikeda et al. (2004) generated transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage and found that they developed severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL (602642)-induced osteoclast differentiation in vitro. Overexpression of NFATC2 or NFATC1 promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.
Umbilical cord blood (UCB)-derived CD4 (186940)-positive T cells differ from adult blood (AB) CD4-positive T cells in part due to reduced expression of NFAT1 and the corresponding reduction in inflammatory cytokine secretion after stimulation. Weitzel et al. (2009) found that endogenous expression of microRNA-184 (MIR184; 613146) in UCB CD4-positive T cells was about 58-fold higher than in AB CD4-positive T cells. Endogenous MIR184 in UCB CD4-positive T cells bound NFAT1 mRNA and blocked its translation, without affecting its degradation. Blocking MIR184 expression in UCB CD4-positive T cells via antisense RNA reversed the negative effects of MIR184 on NFAT1 translation and downstream IL2 transcription. Transfection of precursor MIR184 into AB CD4-positive T cells blocked NFAT1 induction and IL2 production following stimulation. Weitzel et al. (2009) concluded that NFAT1 is an endogenous MIR184 target gene and that MIR184 has a role in the early adaptive immune response.
Calabria et al. (2009) showed that all 4 NFAT family members, including Nfatc2, 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.
Using a yeast 2-hybrid screen, Carneiro et al. (2011) found that IRF2BP2 (615332) interacted with the C-terminal end of NFAT1. GST pull-down analysis confirmed that IRF2BP2 interacted with NFAT1, but not with other NFATs. Immunofluorescence analysis demonstrated nuclear colocalization of IRF2BP2 with activated NFAT1. IRF2BP2 repressed NFAT1-mediated transactivation in activated T cells. The IRF2BP2 RING domain was essential for interaction of IRF2BP2 with NFAT1, and both the RING domain and the zinc finger domain were required for its repressive function. IRF2BP2 had no effect on the stability of NFAT1. Carneiro et al. (2011) concluded that IRF2BP2 is a negative regulator of NFAT1 and proposed that the repression occurs at the transcriptional level.
Hisamitsu et al. (2012) found that human N+/H+ exchanger-1 (NHE1, or SLC9A1; 107310) directly bound calcineurin A (CANA) in the CANA-CANB (PPP3CB; 114106) dimer and promoted serum-induced NFAT nuclear translocation and signaling in human fibroblasts. NHE1 and CANA colocalized in membrane lipid rafts, and calcineurin activity was strongly enhanced at increased pH. NHE1-induced NFAT signaling required Na+/H+ exchange, suggesting that NHE1 may promote calcineurin-NFAT signaling by increasing pH at localized membrane microdomains. Overexpression of NHE1 also induced nuclear translocation of NFAT in primary rat cardiomyocytes and induced hypertrophic signaling.
Li et al. (1995) mapped the human and mouse NFATP genes to chromosome 20 and chromosome 2, respectively, by somatic cell hybrid analysis. They localized the human NFATP gene to 20q13.2-q13.3 by fluorescence in situ hybridization.
In a 21-year-old man, born of consanguineous Middle Eastern parents, with joint contractures, osteochondromas, and B-cell lymphoma (JCOSL; 620232), Sharma et al. (2022) identified a homozygous frameshift mutation in the NFATC2 gene (600490.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation resulted in reduced NFATC2 transcript abundance and undetectable NFAT1 expression in patient-derived lymphocytes. Global transcriptome analysis of patient-derived chondrocytes carrying the mutation showed a notable enrichment in cell proliferation pathways, more resistance to cell death, and higher activation of the inflammatory IL6/JAK/STAT3 signaling pathway compared to controls, resulting in aberrant connective tissue homeostasis. Patient B and T cells had undetectable levels of the NFAT1 protein. Patient B cells showed developmental arrest, with a high proportion of naive B cells and reduced memory B cells; this was associated with increased transcript abundance of genes included in cell proliferation and antiapoptosis, consistent with the patient's development of B-cell lymphoma. Patient CD8+ T cells showed impaired effector functionality in vitro and there was an increase in nonfunctional CD4+ memory T cells. Some of these defects were reversed when wildtype NFATC2 was expressed, confirming that NFAT1 deficiency is the cause of the cellular phenotype. The findings suggested that NFATC2 acts as a tumor suppressor in chondrocytes and B cells.
Li et al. (1995) noted that, based on the conserved syntenic region on human chromosome 20 and mouse chromosome 2, mouse Nfatp was predicted to reside in the vicinity of the mutant locus 'wasted' (wst). Homozygous wst/wst mice displayed a phenotype reminiscent of severe combined immunodeficiency or ataxia-telangiectasia (see 208900), disorders that could therefore be considered candidates for Nfatp mutations.
Whereas Nfatc1-deficient mice have impaired proliferative and T-helper-2 (Th2)-like responses, Nfatc2-deficient mice have modestly enhanced responses with Th2-like characteristics. By fetal liver chimerization in Rag2 (179616)-deficient hosts, Peng et al. (2001) generated mice whose lymphocytes were deficient in both transcription factors. Functional analysis showed that the double knockout (DKO) mice had reasonable proliferative responses and expression of activation markers but were incapable of producing a wide range of cytokines, with the exception of weak production of IL5 (147850), and of expressing CD40 ligand (CD154; 308230) and CD95 ligand (CD95L; 134638) or allogeneic cytotoxicity. Analysis of serum immunoglobulins revealed significantly elevated amounts of IgG1 and IgE, isotypes typically associated with Th2-like immune responses, in DKO mice. The results suggested that NFATC1 and NFATC2 are essential for the maintenance of B-cell homeostasis and differentiation, but are dispensable for T-cell inflammatory activity, as measured by lymphoproliferation and activation marker expression.
Rengarajan et al. (2002) generated Nfatc2 and Nfatc3 (602698) DKO mice. They found that Nfatc2 and Nfatc3 are critical in the determination of the fate of precursor Th cells. DKO T cells intrinsically differentiated into Th2 cytokine-secreting cells, even in the absence of IL4. 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-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 (602699) 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.
Chang et al. (2004) showed that initiation of heart valve morphogenesis in mice required Cnb1 (601302), Nfatc2, Nfatc3, and Nfatc4 to repress Vegf (192240) expression in the myocardium underlying the site of prospective valve formation. Repression of Vegf at mouse embryonic day 9 (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.
In a 21-year-old man, born of consanguineous Middle Eastern parents, with joint contractures, osteochondromas, and B-cell lymphoma (JCOSL; 620232), Sharma et al. (2022) identified a homozygous 4-bp deletion (c.2023_2026delTACC, NM_173091) in exon 8 of the NFATC2 gene, resulting in a frameshift and premature termination (Tyr675ThrfsTer18) in a conserved region in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation resulted in reduced NFATC2 transcript abundance and undetectable NFAT1 expression in patient-derived lymphocytes. Global transcriptome analysis of patient-derived chondrocytes carrying the mutation showed significant up- and downregulation of genes compared to chondrocytes expressing wildtype NFATC2. Mutant cells showed a notable enrichment in cell proliferation pathways, more resistance to cell death, and a higher activation of the inflammatory IL6 (147620)/JAK (147795)/STAT3 (102582) signaling pathway compared to controls, resulting in aberrant connective tissue homeostasis. Patient B and T cells had undetectable levels of the NFAT1 protein. Patient B cells showed developmental arrest, with a high proportion of naive B cells and reduced memory B cells; this was associated with increased transcript abundance of genes included in cell proliferation and anti-apoptosis, consistent with the patient's development of B-cell lymphoma. Patient CD8+ T cells showed impaired effector functionality in vitro and there was an increase in nonfunctional CD4+ memory T cells. Some of these defects were reversed when wildtype NFATC2 was expressed, confirming that NFAT1 deficiency is the cause of the cellular phenotype.
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Sharma, M., Fu, M. P., Lu, H. Y., Sharma, A. A., Modi, B. P., Michalski, C., Lin, S., Dalmann, J., Salman, A., Del Bel, K. L., Waqas, M., Terry, J., and 12 others. Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy. Blood 140: 1858-1874, 2022. [PubMed: 35789258] [Full Text: https://doi.org/10.1182/blood.2022015674]
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