NFAT

Nuclear factor of activated T-cells (NFAT) is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems.

The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5.[1] NFATc1 through NFATc4 are regulated by calcium signaling. Calcium signaling is critical to NFAT activation because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats in the amino termini of NFAT proteins, resulting in a conformational change that exposes a nuclear localization signal, resulting in NFAT nuclear import.

Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as PKA and GSK-3β, must be inactivated for NFAT nuclear retention.

NFAT proteins have weak DNA-binding capacity. Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.[2] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signaling pathways such as ras-MAPK or PKC. In addition, this signaling integration is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects[3][4] discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON.[5]

Breast cancer

NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma [6][7] and NFAT3 (NFATc4) is an inhibitor of cell motility.[8] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion [9] and NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.[8]

References

  1. ↑ Crabtree GR, Olson EN (Apr 2002). "NFAT signaling: choreographing the social lives of cells". Cell. 109 Suppl (2): S67–79. doi:10.1016/S0092-8674(02)00699-2. PMID 11983154.
  2. ↑ Macian F (Jun 2005). "NFAT proteins: key regulators of T-cell development and function". Nature Reviews. Immunology. 5 (6): 472–84. doi:10.1038/nri1632. PMID 15928679.
  3. ↑ Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, et al. (Dec 2002). "Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs". Nature. 420 (6915): 563–73. doi:10.1038/nature01266. PMID 12466851.
  4. ↑ Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, Hayashizaki Y, Tomita M (Jun 2003). "Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection". Genome Research. 13 (6B): 1301–6. doi:10.1101/gr.1011603. PMC 403720Freely accessible. PMID 12819127.
  5. ↑ Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG (Sep 2005). "A strategy for probing the function of noncoding RNAs finds a repressor of NFAT". Science. 309 (5740): 1570–3. doi:10.1126/science.1115901. PMID 16141075.
  6. ↑ Jauliac S, López-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A (Jul 2002). "The role of NFAT transcription factors in integrin-mediated carcinoma invasion". Nature Cell Biology. 4 (7): 540–4. doi:10.1038/ncb816. PMID 12080349.
  7. ↑ Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A (Nov 2005). "Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT". Molecular Cell. 20 (4): 539–50. doi:10.1016/j.molcel.2005.10.033. PMID 16307918.
  8. 1 2 Fougère M, Gaudineau B, Barbier J, Guaddachi F, Feugeas JP, Auboeuf D, Jauliac S (Apr 2010). "NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene". Oncogene. 29 (15): 2292–301. doi:10.1038/onc.2009.499. PMID 20101218.
  9. ↑ Gaudineau B, Fougère M, Guaddachi F, Lemoine F, de la Grange P, Jauliac S (Oct 2012). "Lipocalin 2, the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion". Journal of Cell Science. 125 (Pt 19): 4475–86. doi:10.1242/jcs.099879. PMID 22767506.
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