NFAT

The NFAT (Nuclear Factor of Activated T-Cells) family of transcription factors consists of five members; NFATC1 (NFAT2, NFATc), NFATC2 (NFAT1, NFATp), NFATC3 (NFAT4), NFATC4 (NFAT3) and NFAT5. The transcriptional activity of the NFATC1-C4 isoforms is mediated by the calcium/calmodulin-dependent phosphatase calcineurin. In contrast NFAT5 is calcineurin-independent, being activated by osmotic stress. From here on in NFAT will be used to refer to the NFATC1-C4 isoforms.

Under basal conditions, NFAT is phosphorylated and confined to the cytoplasm. Following an increase in intracellular calcium [Ca²⁺]_i, NFAT is dephosphorylated by calcineurin, exposing its nuclear localization signal (NLS), and resulting in nuclear translocation and entry. As long as [Ca²⁺]_i levels are elevated NFAT remains in the nucleus. A decrease in [Ca²⁺]_i below the threshold results in rephosphorylation of NFAT, masking the NLS and exposing the nuclear export signal (NES), leading to the export of NFAT back into the cytoplasm. In the nucleus NFAT induces the expression of a number of genes including IL-2, IL-3, IL-4, IL-10, TNF-α, IFNγ and COX-2. However NFAT itself has weak DNA binding affinity, therefore it binds to cofactors including AP-1, GATA and MEF to induce transcription.

Several kinases phosphorylate NFAT to regulate its activity. PKA primes NFAT for phosphorylation by 14.3.3 proteins, which maintains its localization in the cytosol. GSK3, PKA, CK1, DYRK1/2 and JNK promote NFAT nuclear export, whereas MEKK1 and CK1 can suppress nuclear export. NFAT is also regulated by sumoylation and proteasome degradation.

The role of NFAT in the immune system is well established, through its induction of cytokine gene expression, and development and activation of T-cells. NFAT is important for the adaptive and innate immune responses, also regulating the activation of macrophages, mast cells and dendritic cells. NFAT is also vital during embryonic development, being important for skeletal, cardiac and nervous system development. Dysregulation of NFAT expression has been implicated in the pathology of inflammatory diseases, such as inflammatory bowel disease, and autoimmune diseases, such as rheumatoid arthritis and lupus. There is also evidence that NFATC1 could be involved in the progression and metastasis of certain cancers, whereas NFATC2 has been shown to induce cell cycle arrest and apoptosis.

NFAT Gene Data