UniProt functional annotation for O95644



	UniProt functional annotation for O95644

UniProt code: O95644.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription. Also controls gene expression in embryonic cardiac cells. Could regulate not only the activation and proliferation but also the differentiation and programmed death of T-lymphocytes as well as lymphoid and non-lymphoid cells (PubMed:10358178). Required for osteoclastogenesis and regulates many genes important for osteoclast differentiation and function (By similarity). {ECO:0000250|UniProtKB:O88942, ECO:0000269|PubMed:10358178}.

Subunit: Member of the multicomponent NFATC transcription complex that consists of at least two components, a pre-existing cytoplasmic component NFATC2 and an inducible nuclear component NFATC1. Other members such as NFATC4, NFATC3 or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. NFATC proteins bind to DNA as monomers (PubMed:9506523). Interacts with HOMER2 and HOMER3; this interaction may compete with calcineurin/PPP3CA-binding and hence prevent NFATC1 dephosphorylation and activation (PubMed:18218901). Interacts with TLE6/GRG6 (By similarity). {ECO:0000250|UniProtKB:O88942, ECO:0000269|PubMed:18218901, ECO:0000269|PubMed:9506523}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16511445}. Nucleus {ECO:0000269|PubMed:16511445}. Note=Cytoplasmic for the phosphorylated form and nuclear after activation that is controlled by calcineurin- mediated dephosphorylation. Rapid nuclear exit of NFATC is thought to be one mechanism by which cells distinguish between sustained and transient calcium signals. The subcellular localization of NFATC plays a key role in the regulation of gene transcription (PubMed:16511445). Nuclear translocation of NFATC1 is enhanced in the presence of TNFSF11. Nuclear translocation is decreased in the presence of FBN1 which can bind and sequester TNFSF11 (By similarity). {ECO:0000250|UniProtKB:O88942, ECO:0000269|PubMed:16511445}.

Tissue specificity: Expressed in thymus, peripheral leukocytes as T- cells and spleen. Isoforms A are preferentially expressed in effector T-cells (thymus and peripheral leukocytes) whereas isoforms B and isoforms C are preferentially expressed in naive T-cells (spleen). Isoforms B are expressed in naive T-cells after first antigen exposure and isoforms A are expressed in effector T-cells after second antigen exposure. Isoforms IA are widely expressed but not detected in liver nor pancreas, neural expression is strongest in corpus callosum. Isoforms IB are expressed mostly in muscle, cerebellum, placenta and thymus, neural expression in fetal and adult brain, strongest in corpus callosum. {ECO:0000269|PubMed:18675896}.

Induction: Only isoforms A are inducibly expressed in T lymphocytes upon activation of the T-cell receptor (TCR) complex. Induced after co- addition of phorbol 12-myristate 13-acetate (PMA) and ionomycin. Also induced after co-addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. Weakly induced with PMA, ionomycin and cyclosporin A.

Domain: Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors.

Domain: The N-terminal transactivation domain (TAD-A) binds to and is activated by Cbp/p300. The dephosphorylated form contains two unmasked nuclear localization signals (NLS), which allow translocation of the protein to the nucleus.

Domain: Isoforms C have a C-terminal part with an additional trans- activation domain, TAD-B, which acts as a transcriptional activator. Isoforms B have a shorter C-terminal part without complete TAD-B which acts as a transcriptional repressor.

Ptm: Phosphorylated by NFATC-kinase and GSK3B; phosphorylation induces NFATC1 nuclear exit and dephosphorylation by calcineurin promotes nuclear import. Phosphorylation by PKA and DYRK2 negatively modulates nuclear accumulation, and promotes subsequent phosphorylation by GSK3B or casein kinase 1. {ECO:0000269|PubMed:12351631, ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:9072970}.

Miscellaneous: [Isoform A-alpha']: Produced by alternative initiation at Met-37 of isoform A-alpha. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription. Also controls gene expression in embryonic cardiac cells. Could regulate not only the activation and proliferation but also the differentiation and programmed death of T-lymphocytes as well as lymphoid and non-lymphoid cells (PubMed:10358178). Required for osteoclastogenesis and regulates many genes important for osteoclast differentiation and function (By similarity). {ECO:0000250\|UniProtKB:O88942, ECO:0000269\|PubMed:10358178}.


Subunit:		Member of the multicomponent NFATC transcription complex that consists of at least two components, a pre-existing cytoplasmic component NFATC2 and an inducible nuclear component NFATC1. Other members such as NFATC4, NFATC3 or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. NFATC proteins bind to DNA as monomers (PubMed:9506523). Interacts with HOMER2 and HOMER3; this interaction may compete with calcineurin/PPP3CA-binding and hence prevent NFATC1 dephosphorylation and activation (PubMed:18218901). Interacts with TLE6/GRG6 (By similarity). {ECO:0000250\|UniProtKB:O88942, ECO:0000269\|PubMed:18218901, ECO:0000269\|PubMed:9506523}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16511445}. Nucleus {ECO:0000269\|PubMed:16511445}. Note=Cytoplasmic for the phosphorylated form and nuclear after activation that is controlled by calcineurin- mediated dephosphorylation. Rapid nuclear exit of NFATC is thought to be one mechanism by which cells distinguish between sustained and transient calcium signals. The subcellular localization of NFATC plays a key role in the regulation of gene transcription (PubMed:16511445). Nuclear translocation of NFATC1 is enhanced in the presence of TNFSF11. Nuclear translocation is decreased in the presence of FBN1 which can bind and sequester TNFSF11 (By similarity). {ECO:0000250\|UniProtKB:O88942, ECO:0000269\|PubMed:16511445}.
Tissue specificity:		Expressed in thymus, peripheral leukocytes as T- cells and spleen. Isoforms A are preferentially expressed in effector T-cells (thymus and peripheral leukocytes) whereas isoforms B and isoforms C are preferentially expressed in naive T-cells (spleen). Isoforms B are expressed in naive T-cells after first antigen exposure and isoforms A are expressed in effector T-cells after second antigen exposure. Isoforms IA are widely expressed but not detected in liver nor pancreas, neural expression is strongest in corpus callosum. Isoforms IB are expressed mostly in muscle, cerebellum, placenta and thymus, neural expression in fetal and adult brain, strongest in corpus callosum. {ECO:0000269\|PubMed:18675896}.
Induction:		Only isoforms A are inducibly expressed in T lymphocytes upon activation of the T-cell receptor (TCR) complex. Induced after co- addition of phorbol 12-myristate 13-acetate (PMA) and ionomycin. Also induced after co-addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. Weakly induced with PMA, ionomycin and cyclosporin A.
Domain:		Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors.
Domain:		The N-terminal transactivation domain (TAD-A) binds to and is activated by Cbp/p300. The dephosphorylated form contains two unmasked nuclear localization signals (NLS), which allow translocation of the protein to the nucleus.
Domain:		Isoforms C have a C-terminal part with an additional trans- activation domain, TAD-B, which acts as a transcriptional activator. Isoforms B have a shorter C-terminal part without complete TAD-B which acts as a transcriptional repressor.
Ptm:		Phosphorylated by NFATC-kinase and GSK3B; phosphorylation induces NFATC1 nuclear exit and dephosphorylation by calcineurin promotes nuclear import. Phosphorylation by PKA and DYRK2 negatively modulates nuclear accumulation, and promotes subsequent phosphorylation by GSK3B or casein kinase 1. {ECO:0000269\|PubMed:12351631, ECO:0000269\|PubMed:16511445, ECO:0000269\|PubMed:9072970}.
Miscellaneous:		[Isoform A-alpha']: Produced by alternative initiation at Met-37 of isoform A-alpha. {ECO:0000305}.