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NFAT5
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1IMH
Identifiers
Aliases	NFAT5, NF-AT5, NFATL1, NFATZ, OREBP, TONEBP, nuclear factor of activated T-cells 5, tonicity-responsive, nuclear factor of activated T-cells 5, nuclear factor of activated T cells 5
External IDs	OMIM: 604708; MGI: 1859333; HomoloGene: 4811; GeneCards: NFAT5; OMA:NFAT5 - orthologs
Gene location (Human)
Chr.	Chromosome 16 (human)
End	69,704,666 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	108,106,149 bp
RNA expression pattern
	Top expressed in
	renal medulla; ; nipple; ; caput epididymis; ; corpus epididymis; ; tail of epididymis; ; Achilles tendon; ; saphenous vein; ; epithelium of colon; ; lactiferous duct; ; vena cava;
	Top expressed in
	ascending aorta; ; aortic valve; ; gastrula; ; medullary collecting duct; ; adrenal gland; ; skin of external ear; ; trachea; ; habenula; ; vestibular membrane of cochlear duct; ; umbilical cord;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	DNA-binding transcription factor activity; RNA polymerase II cis-regulatory region sequence-specific DNA binding; DNA binding; DNA-binding transcription activator activity, RNA polymerase II-specific; protein binding; DNA-binding transcription factor activity, RNA polymerase II-specific; chromatin binding; transcription factor binding;
Cellular component	nucleus; nucleoplasm; cytoplasm; cytosol; transcription regulator complex;
Biological process	regulation of calcineurin-NFAT signaling cascade; cytokine production; positive regulation of gene expression; excretion; regulation of transcription, DNA-templated; transcription by RNA polymerase II; transcription, DNA-templated; signal transduction; positive regulation of transcription by RNA polymerase II; calcineurin-NFAT signaling cascade; response to osmotic stress; cellular response to cytokine stimulus; positive regulation of NIK/NF-kappaB signaling; positive regulation of leukocyte adhesion to vascular endothelial cell;
	Sources:Amigo / QuickGO
Orthologs
	10725
	54446
	ENSG00000102908
	ENSMUSG00000003847
	O94916
	Q9WV30
NM_001113178; NM_006599; NM_138713; NM_138714; NM_173214;
	NM_173215; NM_001367709
	NM_001286260; NM_018823; NM_133957
NP_001106649; NP_006590; NP_619727; NP_619728; NP_775321;
	NP_775322; NP_001354638
	NP_001273189; NP_061293; NP_598718
	Wikidata
View/Edit Human	View/Edit Mouse

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

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.^[5]

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.^[6]^[7] Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production.^[8]

It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla.^[9] Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.^[10]

Structure

The NFAT family consists of five different forms: NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5 (this protein). The proteins in this family are expressed in nearly every tissue in the body and are known transcriptional regulators in cytokine and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system.^[8] cDNA of NFAT5 was first isolated from a human brain cDNA library. Subsequent analysis revealed that NFAT5 is a member of the Rel family, which also consists of NF-κB and NFATc proteins. The largest Rel protein, it consists of nearly 1,500 amino acid residues. Like the other Rel proteins, NFAT5 contains the Rel homology domain, a conserved DNA-binding domain. Outside of the Rel homology domain, no similarities exist between NFAT5 and NF-κB or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import.^[11] Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation.^[8]^[11] Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.

Mechanism of Activation

Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane.^[12] Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6.^[13] This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression.^[12]

It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals.^[9] However, the downstream transcription of the NFAT5 gene by p38 MAPK is currently not yet characterized. It is hypothesized that p38 MAPK phosphorylation activates c-Fos and interferon regulatory factors (IRFs), which bind to AP-1-binding sites and ISRES (Interferon Stimulated Response Element) respectively. Binding to these sites consequently activates the transcription of target genes.^[12]

Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.

Additional Roles

NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.

NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest.^[8]

Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000102908 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000003847 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: NFAT5 nuclear factor of activated T-cells 5, tonicity-responsive".
^ Lee SD, Choi SY, Lim SW, Lamitina ST, Ho SN, Go WY, Kwon HM (2011). "TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress: Organic osmolyte-dependent and -independent pathways". AJP: Renal Physiology. 300 (3): F707–F715. doi:10.1152/ajprenal.00227.2010. PMC 3064130. PMID 21209002.
^ Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM (1999). "Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity". Proc Natl Acad Sci USA. 96 (5): 2538–2542. Bibcode:1999PNAS...96.2538M. doi:10.1073/pnas.96.5.2538. PMC 26820. PMID 10051678.
^ ^a ^b ^c ^d Lee JH, Kim M, Im YS, Choi W, Byeon SH, Lee HK (2008). "NFAT5 induction and its role in hyperosmolar stressed human limbal epithelial cells". Invest. Ophthalmol. Vis. Sci. 49 (5): 1827–1835. doi:10.1167/iovs.07-1142. PMID 18436816.
^ ^a ^b López-Rodríguez C, Antos CL, Shelton JM, Richardson JA, Lin F, Novobrantseva TI, Bronson RT, Igarashi P, Rao A, Olson EN (February 2004). "Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression". Proc. Natl. Acad. Sci. U.S.A. 101 (8): 2392–7. Bibcode:2004PNAS..101.2392L. doi:10.1073/pnas.0308703100. PMC 356961. PMID 14983020.
^ Wang Y, Ko BC, Yang JY, Lam TT, Jiang Z, Zhang J, Chung SK, Chung SS (May 2005). "Transgenic mice expressing dominant-negative osmotic-response element-binding protein (OREBP) in lens exhibit fiber cell elongation defect associated with increased DNA breaks". J. Biol. Chem. 280 (20): 19986–91. doi:10.1074/jbc.M501689200. PMID 15774462.
^ ^a ^b Lopez-Rodríguez C, Aramburu J, Rakeman AS, Rao A (June 1999). "NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7214–9. Bibcode:1999PNAS...96.7214L. doi:10.1073/pnas.96.13.7214. PMC 22056. PMID 10377394.
^ ^a ^b ^c Kino T, Takatori H, Manoli I, Wang Y, Tiulpakov A, Blackman MR, Su YA, Chrousos GP, DeCherney AH, Segars JH (2009). "Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5". Sci Signal. 2 (57): ra5. doi:10.1126/scisignal.2000081. PMC 2856329. PMID 19211510.
^ Kelkar N, Standen CL, Davis RJ (April 2005). "Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways". Mol. Cell. Biol. 25 (7): 2733–43. doi:10.1128/MCB.25.7.2733-2743.2005. PMC 1061651. PMID 15767678.

External links

NFAT5+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: O94916 (Nuclear factor of activated T-cells 5) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000102908 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000003847 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: NFAT5 nuclear factor of activated T-cells 5, tonicity-responsive".

[6] Lee SD, Choi SY, Lim SW, Lamitina ST, Ho SN, Go WY, Kwon HM (2011). "TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress: Organic osmolyte-dependent and -independent pathways". AJP: Renal Physiology. 300 (3): F707–F715. doi:10.1152/ajprenal.00227.2010. PMC 3064130. PMID 21209002.

[miyakawa-7] Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM (1999). "Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity". Proc Natl Acad Sci USA. 96 (5): 2538–2542. Bibcode:1999PNAS...96.2538M. doi:10.1073/pnas.96.5.2538. PMC 26820. PMID 10051678.

[lee-8] Lee JH, Kim M, Im YS, Choi W, Byeon SH, Lee HK (2008). "NFAT5 induction and its role in hyperosmolar stressed human limbal epithelial cells". Invest. Ophthalmol. Vis. Sci. 49 (5): 1827–1835. doi:10.1167/iovs.07-1142. PMID 18436816.

[lopez1-9] López-Rodríguez C, Antos CL, Shelton JM, Richardson JA, Lin F, Novobrantseva TI, Bronson RT, Igarashi P, Rao A, Olson EN (February 2004). "Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression". Proc. Natl. Acad. Sci. U.S.A. 101 (8): 2392–7. Bibcode:2004PNAS..101.2392L. doi:10.1073/pnas.0308703100. PMC 356961. PMID 14983020.

[wang-10] Wang Y, Ko BC, Yang JY, Lam TT, Jiang Z, Zhang J, Chung SK, Chung SS (May 2005). "Transgenic mice expressing dominant-negative osmotic-response element-binding protein (OREBP) in lens exhibit fiber cell elongation defect associated with increased DNA breaks". J. Biol. Chem. 280 (20): 19986–91. doi:10.1074/jbc.M501689200. PMID 15774462.

[lopez2-11] Lopez-Rodríguez C, Aramburu J, Rakeman AS, Rao A (June 1999). "NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7214–9. Bibcode:1999PNAS...96.7214L. doi:10.1073/pnas.96.13.7214. PMC 22056. PMID 10377394.

[kino-12] Kino T, Takatori H, Manoli I, Wang Y, Tiulpakov A, Blackman MR, Su YA, Chrousos GP, DeCherney AH, Segars JH (2009). "Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5". Sci Signal. 2 (57): ra5. doi:10.1126/scisignal.2000081. PMC 2856329. PMID 19211510.

[kelkar-13] Kelkar N, Standen CL, Davis RJ (April 2005). "Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways". Mol. Cell. Biol. 25 (7): 2733–43. doi:10.1128/MCB.25.7.2733-2743.2005. PMC 1061651. PMID 15767678.

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PROFILPELAJAR.COM

NFAT5

Osmotic stress

Structure

Mechanism of Activation

Additional Roles

References

Further reading

External links

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