NFAT5

Nuclear factor of activated T-cells 5, also known as NFAT5, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress.

The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.

Osmotic stress

Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is hypertonic, cells lose water and consequently, shrink. To counteract this, cells increase their sodium uptake in order to lose less water. However, an increase in intracellular ionic concentration is harmful to the cell. Cells can alternatively synthesize enzymes and transporters that increase intracellular concentration of organic osmolytes, which are less toxic than excess ions but which also aid in water retention. Under conditions of hyperosmolarity, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for aldose reductase (AR), the sodium chloride-betaine cotransporter (SLC6A12) the sodium/myo-inositol cotransporter (SLC5A3), the taurine transporter (SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes. Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production.

NFATC2

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

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.

Clinical significance

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) is pro-invasive and pro-migratory in breast carcinoma.

To increase cell motility NFAT1 up-regulates the gene of the Lipocalin 2 expression and modulate the TWEAKR/TWEAK axis.

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. 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.