NFATC2 explained

Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.^[1]

Function

This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-binding protein with a REL-homology region (RHR) and an NFAT-homology region (NHR). This protein is present in the cytosol and only translocates to the nucleus upon T cell receptor (TCR) stimulation, where it becomes a member of the nuclear factors of activated T cells transcription complex. This complex plays a central role in inducing gene transcription during the immune response. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.^[2]

Clinical significance

Translocation forming an in frame fusions product between EWSR1 gene and the NFATc2 gene has been described in bone tumor with a Ewing sarcoma-like clinical appearance. The translocation breakpoint led to the loss of the controlling elements of the NFATc2 protein and the fusion of the N terminal region of the EWSR1 gene conferred constant activation of the protein.^[3]

Interactions

NFATC2 has been shown to interact with MEF2D,^[4] EP300,^[5] IRF4^[6] and Protein kinase Mζ.^[7] Prostaglandin F2alpha stimulates a NFCT2 pathway stimulating growth of skeletal muscle cells.^[8]

Further reading

• Rao A, Luo C, Hogan PG . Transcription factors of the NFAT family: regulation and function . Annual Review of Immunology . 15 . 707–747 . 1997 . 9143705 . 10.1146/annurev.immunol.15.1.707 .
• Crabtree GR . Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT . Cell . 96 . 5 . 611–614 . Mar 1999 . 10089876 . 10.1016/S0092-8674(00)80571-1 . 8817053 . free .
• Horsley V, Pavlath GK . NFAT: ubiquitous regulator of cell differentiation and adaptation . The Journal of Cell Biology . 156 . 5 . 771–774 . Mar 2002 . 11877454 . 2173310 . 10.1083/jcb.200111073 .
• Aramburu J, Azzoni L, Rao A, Perussia B . Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding . The Journal of Experimental Medicine . 182 . 3 . 801–810 . Sep 1995 . 7650486 . 2192167 . 10.1084/jem.182.3.801 .
• Auffray C, Behar G, Bois F, Bouchier C, Da Silva C, Devignes MD, Duprat S, Houlgatte R, Jumeau MN, Lamy B . [IMAGE: molecular integration of the analysis of the human genome and its expression] . Comptes Rendus de l'Académie des Sciences, Série III . 318 . 2 . 263–72 . Feb 1995 . 7757816 .
• Li X, Ho SN, Luna J, Giacalone J, Thomas DJ, Timmerman LA, Crabtree GR, Francke U . Cloning and chromosomal localization of the human and murine genes for the T-cell transcription factors NFATc and NFATp . Cytogenetics and Cell Genetics . 68 . 3–4 . 185–191 . 1995 . 7842733 . 10.1159/000133910 .
• Book: Ho S, Timmerman L, Northrop J, Crabtree GR . Mechanisms of Lymphocyte Activation and Immune Regulation V . Cloning and Characterization of NF-ATc and NF-ATp: The Cytoplasmic Components of NF-AT . Advances in Experimental Medicine and Biology . 1994 . 365 . 167–73 . 7887301 . 10.1007/978-1-4899-0987-9_17 . 978-1-4899-0989-3 .
• Jabado N, Le Deist F, Fisher A, Hivroz C . Interaction of HIV gp120 and anti-CD4 antibodies with the CD4 molecule on human CD4+ T cells inhibits the binding activity of NF-AT, NF-kappa B and AP-1, three nuclear factors regulating interleukin-2 gene enhancer activity . European Journal of Immunology . 24 . 11 . 2646–2652 . Nov 1994 . 7957556 . 10.1002/eji.1830241112 . 30435577 .
• Vacca A, Farina M, Maroder M, Alesse E, Screpanti I, Frati L, Gulino A . Human immunodeficiency virus type-1 tat enhances interleukin-2 promoter activity through synergism with phorbol ester and calcium-mediated activation of the NF-AT cis-regulatory motif . Biochemical and Biophysical Research Communications . 205 . 1 . 467–474 . Nov 1994 . 7999066 . 10.1006/bbrc.1994.2689 .
• Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, Curran T, Rao A . The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun . Nature . 365 . 6444 . 352–355 . Sep 1993 . 8397339 . 10.1038/365352a0 . 1993Natur.365..352J . 4283223 .
• Luo C, Burgeon E, Carew JA, McCaffrey PG, Badalian TM, Lane WS, Hogan PG, Rao A . Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes . Molecular and Cellular Biology . 16 . 7 . 3955–66 . Jul 1996 . 8668213 . 231392 . 10.1128/mcb.16.7.3955.
• Di Somma MM, Majolini MB, Burastero SE, Telford JL, Baldari CT . Cyclosporin A sensitivity of the HIV-1 long terminal repeat identifies distinct p56lck-dependent pathways activated by CD4 triggering . European Journal of Immunology . 26 . 9 . 2181–2188 . Sep 1996 . 8814265 . 10.1002/eji.1830260933 . 23430217 .
• Copeland KF, McKay PJ, Rosenthal KL . Suppression of the human immunodeficiency virus long terminal repeat by CD8+ T cells is dependent on the NFAT-1 element . AIDS Research and Human Retroviruses . 12 . 2 . 143–148 . Jan 1996 . 8834464 . 10.1089/aid.1996.12.143 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Hodge MR, Chun HJ, Rengarajan J, Alt A, Lieberson R, Glimcher LH . NF-AT-Driven interleukin-4 transcription potentiated by NIP45 . Science . 274 . 5294 . 1903–1905 . Dec 1996 . 8943202 . 10.1126/science.274.5294.1903 . 1996Sci...274.1903H . 29436825 .
• Lyakh L, Ghosh P, Rice NR . Expression of NFAT-family proteins in normal human T cells . Molecular and Cellular Biology . 17 . 5 . 2475–84 . May 1997 . 9111316 . 232096 . 10.1128/mcb.17.5.2475.
• Amasaki Y, Masuda ES, Imamura R, Arai K, Arai N . Distinct NFAT family proteins are involved in the nuclear NFAT-DNA binding complexes from human thymocyte subsets . Journal of Immunology . 160 . 5 . 2324–33 . Mar 1998 . 10.4049/jimmunol.160.5.2324 . 9498773 . 19932048 . free .
• Chen L, Glover JN, Hogan PG, Rao A, Harrison SC . Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA . Nature . 392 . 6671 . 42–48 . Mar 1998 . 9510247 . 10.1038/32100 . 1998Natur.392...42C . 4305535 .

Notes and References

1. Northrop JP, Ho SN, Chen L, Thomas DJ, Timmerman LA, Nolan GP, Admon A, Crabtree GR . NF-AT components define a family of transcription factors targeted in T-cell activation . Nature . 369 . 6480 . 497–502 . Jun 1994 . 8202141 . 10.1038/369497a0 . 1994Natur.369..497N . 9920546 .
2. Web site: Entrez Gene: NFATC2 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2.
3. Szuhai K, Ijszenga M, de Jong D, Karseladze A, Tanke HJ, Hogendoorn PC . The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology . Clinical Cancer Research . 15 . 7 . 2259–68 . Apr 2009 . 19318479 . 10.1158/1078-0432.CCR-08-2184 . free .
4. Youn HD, Chatila TA, Liu JO . Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis . The EMBO Journal . 19 . 16 . 4323–31 . Aug 2000 . 10944115 . 302027 . 10.1093/emboj/19.16.4323 .
5. García-Rodríguez C, Rao A . Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP) . The Journal of Experimental Medicine . 187 . 12 . 2031–6 . Jun 1998 . 9625762 . 2212364 . 10.1084/jem.187.12.2031 .
6. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH . Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression . The Journal of Experimental Medicine . 195 . 8 . 1003–12 . Apr 2002 . 11956291 . 2193700 . 10.1084/jem.20011128 .
7. San-Antonio B, Iñiguez MA, Fresno M . Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity . The Journal of Biological Chemistry . 277 . 30 . 27073–80 . Jul 2002 . 12021260 . 10.1074/jbc.M106983200 . free .
8. Horsley V, Pavlath GK. Prostaglandin F2(alpha) stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway. . J Cell Biol . 2003 . 161 . 1 . 111–8 . 12695501 . 10.1083/jcb.200208085 . 2172881 .