NFAT

Nuclear factor of activated T-cells (NFAT) is 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. NFAT was first discovered as an activator for the transcription of interleukin-2 in T cells, as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders. Nuclear factor of activated T-cells (NFAT) is 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. NFAT was first discovered as an activator for the transcription of interleukin-2 in T cells, as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders. The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5. NFATc1 through NFATc4 are regulated by calcium signaling, and are known as the classical members of the NFAT family. NFAT5 is a more recently discovered member of the NFAT family that has special characteristics that differentiate it from other NFAT members. 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. NFATc1 and NFAT c2 mRNAs are expressed in peripheral lymphoid tissue, while NFATc4 is highly expressed in the thymus. NFATc3 mRNA however, is expressed at low levels in lymphoid tissue. Phosphorylation and dephosphorylation is key for controlling NFAT function by masking and unmasking nuclear localization signals, as shown by the high number of phosphorylation sites in the NFAT regulatory domain. 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. 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 discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON. The best known classes of binding sites for NFAT are the formation of a cooperative complex with AP-1 or other bZIP proteins to form a composite NFAT:AP-1 site that is involved in gene transcription in immune cells and the binding to sites for conventional Rel-family proteins. NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites, which indicates that higher order, synergistic interactions between the relevant proteins in a cooperative complex is needed for effective transcription. The best known classes of binding sites for NFAT are the formation of a cooperative complex with AP-1 or other bZIP proteins and the binding to sites for conventional Rel-family proteins. NFAT5 cannot form complexes with AP-1 proteins, however all NFAT proteins recognize similar DNA binding sites in gene regulatory regions.