[4] On the other hand, NFAT5 lacks a crucial part of the N-terminal regulatory domain which in the aforementioned group harbours the essential CN binding site.
When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes.
[5] Although phosphorylation and dephosphorylation are 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, this dephosphorylation cannot occur without an influx of calcium ions.
The IP3 is especially important for calcium influx because it binds to a IP3 receptor located in the membrane of the endoplasmic reticulum (ER).
This causes a short sharp increase in calcium concentration in cytosol as the ions leave the ER through the IP3 receptor.
Only this longer inflow of calcium ions is capable of fully activating NFAT through the CaM/CN mediated dephosphorylation as stated above.
In this alternative activation SOCE is insignificant as shown by the fact that cyclosporine (CsA), which inhibits CN mediated dephosphorylation, does not abrogate this pathway.
[6] Nuclear import of NFAT and its subsequent export is dependent on the calcium level inside of a cell.
[8] Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.
[12] NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites which indicates that higher order synergistic interactions between relevant proteins in a cooperative complex is needed for effective transcription.
[13][3] T-cell receptor (TCR) stimulation causes the dephosphorylation of NFAT which in almost every kind of T cell then forms a complex with AP-1 (except in Tregs).
This complex depending on the cytokine context then activates the key transcription factors of the distinct T cell subpopulations: T-bet for Th1, GATA3 for Th2, RORγ for Th17 and BATF for Tfh.
This complex afterwards activates transcription of BATF which then also binds to NFAT and together with other proteins like IRF4 commences production of Tfh indespensable molecules: CXCR5, ICOS, Bcl6 and IL-21.
In B cells mainly NFATc1 and after activation also NFATc2 and NFAT2/αA are expressed and fulfil important functions like antigen presentation, proliferation, and apoptosis.
If for instance a specific B cell knockout of both STIM proteins is carried out, SOCE is completely abolished and therefore NFAT signalling as well.
[6] The Ca2+ dependent calcineurin/NFAT signalling pathway has been found to be important in neuronal growth and axon guidance during vertebrate development.
NFAT works with neurotrophic signalling to regulate axon outgrowth in several neuronal populations.
Additionally, NFAT transcription complexes integrate neuronal growth with guidance cues such as netrin to facilitate the formation of new synapses, helping to build neural circuits in the brain.
NFAT also plays a role in Rheumatoid Arthritis (RA), an autoimmune disease that has a strong pro-inflammatory component.
[1] Due to its essential role in the production of the T cell proliferative cytokine IL-2, NFAT signalling is an important pharmacological target for the induction of immunosuppression.