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NFATC2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2)

Written2012-07Sietse J Luk, Pancras CW Hogendoorn, Karoly Szuhai
Department of Molecular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2330 RC, Leiden, The Netherlands (SJL, KS); Department of Pathology, Leiden University Medical Center, Einthovenweg 20, 2330 RC, Leiden, The Netherlands (PCWH)

(Note : for Links provided by Atlas : click)


HGNC Alias symbNF-ATP
HGNC Previous namenuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2
 nuclear factor of activated T-cells 2
LocusID (NCBI) 4773
Atlas_Id 44004
Location 20q13.2  [Link to chromosome band 20q13]
Location_base_pair Starts at 51386963 and ends at 51542719 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NFATC2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EWSR1 (22q12.2)::NFATC2 (20q13.2)FUS (16p11.2)::NFATC2 (20q13.2)MEF2A (15q26.3)::NFATC2 (20q13.2)
NFATC2 (20q13.2)::DTX3L (3q21.1)NFATC2 (20q13.2)::EWSR1 (22q12.2)NFATC2 (20q13.2)::RAE1 (20q13.31)


  Figure 1: Genomic organization of NFATC2. The NFATC2 gene is localized on the minus (-) strand of the 20q13.2 chromosome. Black boxes resemble untranslated regions (UTR's); colors of translated exons correspond to protein domains (see later); boxe sizes are in proportion to exon size.
Description The NFATC2 gene consists of 11 exons of which the last is the biggest. There are five known transcripts, varying from 7525 to 620 base pairs of which the largest four lead to a protein product (ensembl, last viewed at 10-04-2012) (Macian, 2005).
Transcription Transcription of the gene is from the - strand. Transcribed sequence contains both a 5'and a 3'-UTR region. The 5-UTR is located in exon 10 and the full exon 11 and is > 4500 bases in size. The large UTR indicates transcription control by small non-coding RNA and/or large non-coding RNA sequences (ensembl, last viewed at 10-04-2012).


  Figure 2: The NFATC2 protein. NHR, NFAT homology region; RHR, REL-homology region; NLS, nuclear localization signal; SRR, serine rich region; TAD, trans activation domain (Macian, 2005; Szuhai et al., 2009).
Description NFATc2 is part of the NFAT family of transcription factors. The conserved region of all NFAT proteins consists of two domains. The first is the NFAT Homology region (NHR) which is the regulatory domain. It contains a strong transactivation domain and many serine residues that are phosphorylated when the protein is inactive and resides in the cytoplasm. There are two serine rich regions (SRRs) and three SPXX-repeat motifs (SPs), where X stands for any amino acid. Calcineurin and NFAT kinases regulate the activity of the NFAT proteins by determining the phosphorylation status of the serine residues, interacting with NFAT proteins at the NHR.
Another, highly conserved region of the NFAT family is the DNA binding domain that is structurally related to the DNA binding domain of the Rel-Family of transcription factors. This domain, called the REL homology region (RHR) is also responsible for binding partner proteins like the AP1 complex.
There are three alternative splice variants of the NFATC2 protein, all of which occur in the C-terminal domain of the protein (Macian, 2005).
Expression Inactive NFATC2 normally resides in the cytoplasm where the serine residues in the NHR are phosphorylated. This phosphorylated state of the NHR results in configuration changes of the protein shielding the nuclear localisation signal (NLS). Activation of NFATC2 is regulated by a pathway including calcium influx to the cytoplasm, calmodulin and calcineurin. In response to various stimuli, calcium enters the cytoplasm from the environment and intracellular stores. Calcium binds calmodulin and this complex activates calcineurin. The activated calcineurin will dephosphorylate the SRRs and SPs of the NHR, resulting in the exposure of the NLS and translocation of the protein to the nucleus. Translocated NFAT binds to consensus DNA sites (WGGAAANHN (H is not G, N is any of the four nucleotides)) and control gene transcription with the help of other nuclear complexes such as the AP1 protein complex (Macian, 2005).
Several kinases have been identified to rephosphorylate NFAT proteins at multiple sites, thereby controlling their nuclear shuttling. These kinases include glycogen-synthase kinase 3 (GSK3), casein kinase 1 (CK1), p38, and JUN N-terminal kinase (JNK). Some of them act as maintenance kinases, to keep the NFAT proteins in the cytosol in a fully phosphorylated state, preventing them from nuclear shuttling. Others act as export kinases; they rephosphorylate NFAT in the nucleus and thereby promote the nuclear export of NFAT, stopping the NFAT driven transcription after calcineurin activity declines.
Another regulatory mechanism has been discovered for NFAT proteins which uses a non-coding RNA (ncRNA). Functional analysis of ncRNAs found a Non-coding repressor of NFAT (NRON). When NRON was deactivated by small hairpin RNA (shRNA), a dramatic increase in NFAT activity was measured. NRON directly binds to 11 proteins, of which four are repressors of NFAT. NRON probably interacts with the nuclear shuttling of NFAT proteins which is demonstrated by an increase in nuclear localisation upon treatment with NRON shRNA (Rao et al., 1997; Willingham et al., 2005; Macian, 2005).
At this moment, 8 different microRNA's, which target 5 locations on the NFATC2 gene have been discovered (ensembl last viewed at 10-04-2012).
Localisation In its inactive form, NFATC2 resides in the cytoplasm. When activated it translocates to the nucleus (Macian, 2005).
Function NFATC2 is a transcription factor that forms complexes with other nuclear proteins including the AP-1 complex and regulates transcription of a large number of genes. It thereby regulates many processes including cell differentiation, migration and angiogenesis. It is, together with the other NFAT's, essential for the development of multiple organ systems, including the nerve and immune system, the heart and skeletal muscles, the vasculature, the lungs and the skeletal structures. Because of their multiple functions, dysfunction of NFAT's may play a role in pathobiology of cancer (Wu et al., 2007; Macian, 2005).
Homology NFATC2 shows great similarity with the NFATC1, NFATC3 and NFATC4 proteins. The RHR shows great similarity with the DNA binding sites of proteins of the REL family of transcription factors (Hogan et al., 2003).

Implicated in

Entity Ewing sarcomalike small blue round cell tumour
Note The NFATC2 gene was found to be involved in a chromosomal translocation found in an Ewing sarcomalike small blue round cell tumour. In this entity, the EWSR1 gene is fused in frame with the NFATC2 gene resulting in a chimera gene. In addition, an amplification of the chimera gene has been observed, something that hasn't been seen in other EWSR1 gene translocation tumours (Szuhai et al., 2007; Szuhai et al., 2009).
Figure 3: Translocation at DNA level. Numbers correspond to exon numbers; black regions are untranslated regions; box sizes are in proportion to exon size; colors correspond to protein domains.
Abnormal Protein In the chimera protein, the regulatory domain of the EWSR1 protein is fused with the functional domain of the NFATC2 gene. EWSR1 is a member of the TET family of proteins and has a predominantly nuclear localization. It contains a domain for nucleic acid binding and has, among others a function in RNA polymerase II- mediated transcription and premRNA splicing. In the chimera protein, the N-terminal regulatory domain of NFATC2 is completely replaced by the regulatory domain of the EWSR1 protein. In this way, the localization of the NFATC2 containing chimera is not under the control of the Ca2+ dependent calcineurin/calmodulin phosphorylation. Instead, the chimera gains the strong, highly conserved NLS of EWSR1 which leads to uncontrolled shuttling of the chimera to the nucleus. Also, because the transcription of the chimera is under control of the regulatory domain of EWSR1, the regulatory loop of NFATC2 is abrogated. The RHR of NFATC2, which is responsible for DNA binding and the complex formation with other proteins such as the AP-1 complex is completely retained in the chimera (Szuhai et al., 2009; Tan et al., 2009).
Figure 4: Translocation at protein level. Yellow box corresponds to nuclear localisation signal.
Oncogenesis Some homology can be seen between this recently described small blue round cell tumour and Ewing sarcoma. In Ewing Sarcoma, the EWSR1 gene forms a chimera with members of the ETS family. In this entity, the member of the ETS family is replaced by NFATC2. The consensus sequence for the ETS family contains a core domain of GGAW (W is a wobble for A or T), whereas the conserved core domain for NFAT is WGGAAANHN (H is not G, N is any of the four nucleotides). There is complete overlap between the core domain of ETS and NFAT for the GGAA sequence variant, which might be responsible for the similar histological features of tumors despite the involvement of different transcription factor families.
Both ETS family members, the EWS/FLI chimera and NFATC2 form complexes with AP-1. It has yet to be determined whether the EWSR1/NFATC2 chimera does this as well (Szuhai et al., 2009; Sankar et al., 2011).
Entity Non small cell lung cancer
Note The expression of NFATC2 in non small cell lung cancer is positively correlated with progression in TNM stage: the higher the TNM stage, the higher the expression of NFATC2. High expression of NFATC2 is also a predictor for a low post-operative survival indicating that it promotes lung cancer and metastasis by serving as an oncogene (Chen et al., 2011).
Entity Breast cancer
Note Stat 5 signalling.
Stat5, a member of the signal transducers and activators of transcription (stat) family of proteins, promotes tumor growth, but suppresses metastasis in breast cancer. NFATC2 has exactly the opposite effects; it inhibits tumor growth and promotes tumor metastasis. NFATC2 down regulates the Stat5 signaling pathway and vice versa. Also, the expression of the two genes is negatively correlated in a breast cancer progression tissue micro array (TMA). NFATC2 is expressed more in metastatic tissue than in normal tissue and primary tumor but Stat5 is the other way around (Zheng et al., 2011).
Entity Various cancers
Note Regulation of tissue micro environment.
Experiments in mice have been performed to assess the influence of NFATC2 on metastasis formation and growth. Therefore NFATC2 null(-/-) mice were compared with NFATC2 normal(+/+) mice after intravenous injection of F16F10 melanoma cells. NFATC2-/- mice showed less and smaller metastases. Both the NFATC2 null(-/-) and wild type mice were treated with a wild type bone marrow transplantation to make sure differences were caused by the lack of NFATC2 in the lung parenchyma and not because of a dysfunction of the immune system (Werneck et al., 2011).
In hepatocellular carcinoma, colon carcinoma and breast cancer, NFATC2 plays an important role in regulating genes that affect tumoral phenotype such as cyclooxygenase-2 (COX-2). COX-2 is a key regulator in the expression of matrix metalloproteinase 1 and matrix metalloproteinase 2 and thereby of tumour invasion (Lara-Pezzi et al., 2002; Duque et al., 2005; Yiu et al., 2006).
Entity α6β4 integrin signalling
Note NFAT signalling (including NFATC2 signalling) is part of the pathway that is activated in α6β4 integrin mediated cell invasion and migration. This pathway leads to the expression of autotoxin. It is suggested that α6β4 integrin mediated cell invasion is at least in part due to the increased expression of autotoxin (Jauliac et al., 2002; Chen et al., 2005).


Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells.
Chen M, O'Connor KL.
Oncogene. 2005 Jul 28;24(32):5125-30.
PMID 15897878
Expression and unique functions of four nuclear factor of activated T cells isoforms in non-small cell lung cancer.
Chen ZL, Zhao SH, Wang Z, Qiu B, Li BZ, Zhou F, Tan XG, He J.
Chin J Cancer. 2011 Jan;30(1):62-8.
PMID 21192845
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, Iniguez MA.
J Biol Chem. 2005 Mar 11;280(10):8686-93. Epub 2005 Jan 4.
PMID 15632146
Transcriptional regulation by calcium, calcineurin, and NFAT.
Hogan PG, Chen L, Nardone J, Rao A.
Genes Dev. 2003 Sep 15;17(18):2205-32. (REVIEW)
PMID 12975316
The role of NFAT transcription factors in integrin-mediated carcinoma invasion.
Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A.
Nat Cell Biol. 2002 Jul;4(7):540-4.
PMID 12080349
The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression.
Lara-Pezzi E, Gomez-Gaviro MV, Galvez BG, Mira E, Iniguez MA, Fresno M, Martinez-A C, Arroyo AG, Lopez-Cabrera M.
J Clin Invest. 2002 Dec;110(12):1831-8.
PMID 12488433
NFAT proteins: key regulators of T-cell development and function.
Macian F.
Nat Rev Immunol. 2005 Jun;5(6):472-84. (REVIEW)
PMID 15928679
Transcription factors of the NFAT family: regulation and function.
Rao A, Luo C, Hogan PG.
Annu Rev Immunol. 1997;15:707-47. (REVIEW)
PMID 9143705
Promiscuous partnerships in Ewing's sarcoma.
Sankar S, Lessnick SL.
Cancer Genet. 2011 Jul;204(7):351-65. doi: 10.1016/j.cancergen.2011.07.008. (REVIEW)
PMID 21872822
Detection and molecular cytogenetic characterization of a novel ring chromosome in a histological variant of Ewing sarcoma.
Szuhai K, IJszenga M, Tanke HJ, Taminiau AH, de Schepper A, van Duinen SG, Rosenberg C, Hogendoorn PC.
Cancer Genet Cytogenet. 2007 Jan 1;172(1):12-22.
PMID 17175374
The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology.
Szuhai K, Ijszenga M, de Jong D, Karseladze A, Tanke HJ, Hogendoorn PC.
Clin Cancer Res. 2009 Apr 1;15(7):2259-68. Epub 2009 Mar 24.
PMID 19318479
The TET family of proteins: functions and roles in disease.
Tan AY, Manley JL.
J Mol Cell Biol. 2009 Dec;1(2):82-92. Epub 2009 Sep 24. (REVIEW)
PMID 19783543
NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis.
Werneck MB, Vieira-de-Abreu A, Chammas R, Viola JP.
Cancer Immunol Immunother. 2011 Apr;60(4):537-46. Epub 2011 Jan 12.
PMID 21225259
A strategy for probing the function of noncoding RNAs finds a repressor of NFAT.
Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG.
Science. 2005 Sep 2;309(5740):1570-3.
PMID 16141075
NFAT signaling and the invention of vertebrates.
Wu H, Peisley A, Graef IA, Crabtree GR.
Trends Cell Biol. 2007 Jun;17(6):251-60. Epub 2007 May 10.
PMID 17493814
NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2.
Yiu GK, Toker A.
J Biol Chem. 2006 May 5;281(18):12210-7. Epub 2006 Feb 27.
PMID 16505480
Negative cross talk between NFAT1 and Stat5 signaling in breast cancer.
Zheng J, Fang F, Zeng X, Medler TR, Fiorillo AA, Clevenger CV.
Mol Endocrinol. 2011 Dec;25(12):2054-64. Epub 2011 Sep 29.
PMID 21964595


This paper should be referenced as such :
Luk, Sietse J ; Hogendoorn, PCW ; Szuhai, K
NFATC2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(1):35-39.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]

External links

HGNC (Hugo)NFATC2   7776
Atlas Explorer : (Salamanque)NFATC2
Entrez_Gene (NCBI)NFATC2    nuclear factor of activated T cells 2
GeneCards (Weizmann)NFATC2
Ensembl hg19 (Hinxton)ENSG00000101096 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000101096 [Gene_View]  ENSG00000101096 [Sequence]  chr20:51386963-51542719 [Contig_View]  NFATC2 [Vega]
ICGC DataPortalENSG00000101096
Genatlas (Paris)NFATC2
SOURCE (Princeton)NFATC2
Genetics Home Reference (NIH)NFATC2
Genomic and cartography
GoldenPath hg38 (UCSC)NFATC2  -     chr20:51386963-51542719 -  20q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NFATC2  -     20q13.2   [Description]    (hg19-Feb_2009)
GoldenPathNFATC2 - 20q13.2 [CytoView hg19]  NFATC2 - 20q13.2 [CytoView hg38]
Genome Data Viewer NCBINFATC2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK025758 AK226146 AK304147 AY927566 BC136418
RefSeq transcript (Entrez)NM_001136021 NM_001258292 NM_001258294 NM_001258295 NM_001258296 NM_001258297 NM_012340 NM_173091
Consensus coding sequences : CCDS (NCBI)NFATC2
Gene ExpressionNFATC2 [ NCBI-GEO ]   NFATC2 [ EBI - ARRAY_EXPRESS ]   NFATC2 [ SEEK ]   NFATC2 [ MEM ]
Gene Expression Viewer (FireBrowse)NFATC2 [ Firebrowse - Broad ]
GenevisibleExpression of NFATC2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4773
GTEX Portal (Tissue expression)NFATC2
Human Protein AtlasENSG00000101096-NFATC2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)NFATC2
Human Protein Atlas [tissue]ENSG00000101096-NFATC2 [tissue]
Protein Interaction databases
Complex Portal (EBI) CPX-480 AP-1 transcription factor complex FOS-JUN-NFATC2
Ontologies - Pathways
PubMed237 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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