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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 immune, cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells (as a regulator of T cell immune response) but has since been found to play an important role in regulating many more 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 signalling, 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 signalling is critical to activation of NFATc1-4 because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats which are also present in the N-terminus of the NFAT proteins. This dephosphorylation results in a conformational change that exposes a nuclear localization signal which promotes nuclear translocation.
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. This makes NFAT5 activation completely independent of calcium signalling. It is, however, controlled by MAPK during osmotic stress. When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in the kidney medulla, skin and eyes but it can be also found in the thymus and activated lymphocytes.
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 classical signalling relies on activation of phospholipase C (PLC) through different receptors like the T-cell receptor (TCR) (PLCG1[citation needed]) or B-cell receptor (BCR) (PLCG2[citation needed]). This activation leads to release of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). 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. However, this is not enough to activate NFAT signalling. The release of calcium ions from ER is sensed by STIM proteins which are ER transmembrane proteins. Under normal circumstances the STIM proteins bind calcium ions but if most of them are released from ER the bound ions are released from the STIM proteins as well. This causes them to oligomerize and subsequently interact with ORAI1 which is an indispensable protein of CRAC complex. This complex serves as a channel which selectively allows the influx of calcium ions from outside of a cell. This phenomenon is called store-operated calcium entry (SOCE). Only this longer inflow of calcium ions is capable of fully activating NFAT through the CaM/CN mediated dephosphorylation as stated above.
Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can also be activated by an alternative pathway. This pathway was until now proofed only for NFATc2. 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. The reason for this is that it is activated through IL7R which leads to subsequent phosphorylation of single tyrosine in NFAT mediated by Jnk3 kinase a member of MAPK kinase subfamily.
Nuclear import of NFAT and its subsequent export is dependent on the calcium level inside of a cell. If the calcium level drops, the exporting kinases in a nucleus such as PKA, CK1 or GSK-3β rephosphorylate NFAT. This causes that NFAT reverts into its inactive state and is exported back to the cytosol where maintenance kinases finish the rephosphorylation in order to keep it in the inactivated state.
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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 immune, cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells (as a regulator of T cell immune response) but has since been found to play an important role in regulating many more 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 signalling, 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 signalling is critical to activation of NFATc1-4 because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats which are also present in the N-terminus of the NFAT proteins. This dephosphorylation results in a conformational change that exposes a nuclear localization signal which promotes nuclear translocation.
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. This makes NFAT5 activation completely independent of calcium signalling. It is, however, controlled by MAPK during osmotic stress. When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in the kidney medulla, skin and eyes but it can be also found in the thymus and activated lymphocytes.
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 classical signalling relies on activation of phospholipase C (PLC) through different receptors like the T-cell receptor (TCR) (PLCG1[citation needed]) or B-cell receptor (BCR) (PLCG2[citation needed]). This activation leads to release of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). 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. However, this is not enough to activate NFAT signalling. The release of calcium ions from ER is sensed by STIM proteins which are ER transmembrane proteins. Under normal circumstances the STIM proteins bind calcium ions but if most of them are released from ER the bound ions are released from the STIM proteins as well. This causes them to oligomerize and subsequently interact with ORAI1 which is an indispensable protein of CRAC complex. This complex serves as a channel which selectively allows the influx of calcium ions from outside of a cell. This phenomenon is called store-operated calcium entry (SOCE). Only this longer inflow of calcium ions is capable of fully activating NFAT through the CaM/CN mediated dephosphorylation as stated above.
Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can also be activated by an alternative pathway. This pathway was until now proofed only for NFATc2. 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. The reason for this is that it is activated through IL7R which leads to subsequent phosphorylation of single tyrosine in NFAT mediated by Jnk3 kinase a member of MAPK kinase subfamily.
Nuclear import of NFAT and its subsequent export is dependent on the calcium level inside of a cell. If the calcium level drops, the exporting kinases in a nucleus such as PKA, CK1 or GSK-3β rephosphorylate NFAT. This causes that NFAT reverts into its inactive state and is exported back to the cytosol where maintenance kinases finish the rephosphorylation in order to keep it in the inactivated state.