NFATC1 (NFATc1, NFAT2) is a calcium-regulated transcription factor of the NFAT family, with an N-terminal NFAT homology (regulatory) region carrying serine-rich phosphorylation motifs and the PxIxIT and LxVP calcineurin-docking sites, a central Rel homology DNA-binding domain that recognizes GGAA-core NFAT sites, and variable N- and C-terminal transactivation domains generated by alternative promoters and splicing. In resting cells NFATC1 is heavily phosphorylated and held in the cytoplasm. Receptor-triggered phospholipase C activity (for example PLCG1 downstream of the T cell antigen receptor) produces IP3 and store-operated Ca2+ entry; Ca2+/calmodulin-activated calcineurin docks on NFATC1 and dephosphorylates it, exposing its nuclear localization signal and driving nuclear import. Rephosphorylation by GSK3, CK1 and DYRK kinases returns it to the cytoplasm. In the nucleus NFATC1 binds DNA weakly as a monomer and acts mainly cooperatively with partners such as AP-1 (FOS/JUN) at composite elements, as well as with ATF/CREB bZIP factors, PU.1, MITF, GATA4 and others, to activate RNA polymerase II target genes. NFATC1 is pleiotropic: in T lymphocytes it drives activation-induced cytokine genes such as IL2 and IL4 and supports effector and memory responses (with an autoregulated inducible short isoform, NFATc1/alphaA, that is induced by chronic antigen stimulation and promotes survival of exhausted CD8+ T cells), and contributes to TH2 differentiation; downstream of RANKL it is the master transcriptional switch of osteoclast terminal differentiation (inducing genes such as cathepsin K); and in the endocardium it is required for semilunar heart valve formation. It also regulates gene expression in other cell types, including vascular smooth muscle and mesangial cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | IDA PMID:15304486 Essential role of p38 mitogen-activated protein kinase in ca... | ACCEPT | Summary: Chromatin localization of NFATc1 in RANKL-stimulated osteoclast precursors, where it associates with PU.1 at the cathepsin K promoter. Reason: NFATc1 is a sequence-specific DNA-binding transcription factor that acts on chromatin at target promoters once nuclear; the curator read the full text (only the abstract is cached), and the location is biologically correct. Also consistent with the chromatin-fraction-restricted NFATC1 complexes in PMID:25609649. Supporting Evidence: PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. PMID:25609649 NFATC1 still only appeared in chromatin fractions |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of chromatin location to a Rel-homology-domain sequence-specific transcription factor. Reason: Correct: the active, nuclear pool of NFATC1 is chromatin-bound, and proteomic fractionation found NFATC1 only in the chromatin fraction. Supporting Evidence: PMID:25609649 NFATC1 still only appeared in chromatin fractions |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: RNA polymerase II cis-regulatory region sequence-specific DNA binding, inherited across the NFAT Rel-homology family node. Reason: Core molecular activity. The Rel homology region binds GGAA-core NFAT sites in Pol II promoters such as the IL2 ARRE2 element; the phylogenetic node covering NFATC1-4 is well placed. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. file:human/NFATC1/NFATC1-deep-research-falcon.md NFATc1 recognizes the consensus DNA motif 5β²-GGAA(A)-3β² through its Rel homology domain |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nfatc1: RNA polymerase II cis-regulatory region sequence-specific DNA binding. Reason: Same core DNA-binding activity as the IBA row; supported by the human NFATC1 DBD-DNA structure and ChIP at the MT1-MMP promoter. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. PMID:14979875 Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: Core function. NFATC1 is a Pol II-specific DNA-binding transcription factor (IL2, IL4, MT1-MMP, cathepsin K and many other targets). Supporting Evidence: PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based (ISA) assignment of Pol II-specific DNA-binding transcription factor activity. Reason: Correct classification of NFATC1 as a Rel-homology-domain DbTF (TFClass 6.1.3, NFAT-related factors). Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nfatc1: DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: Correct; consistent with human experimental data. Supporting Evidence: PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nfatc1: DNA-binding transcription activator activity, RNA polymerase II-specific. Reason: Most precise statement of the core molecular function: NFATC1 is predominantly a transcriptional activator of its Pol II target genes (IL2 promoter activation, MT1-MMP transactivation), usually in cooperation with AP-1 or other partners. Supporting Evidence: PMID:8202141 Expression of the full-length complementary DNA encoding NF-ATc activates the interleukin (IL-2) promoter in non-T lymphocytes PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. |
| GO:0003180 aortic valve morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: aortic valve morphogenesis (Nfatc1-null mice lack semilunar valves). Reason: NFATc1 is required in the endocardium for semilunar valve formation; as the transcription factor executing a calcineurin-dependent developmental program it plausibly participates (by regulating gene expression) rather than being merely necessary. This is a genuine but pleiotropic developmental role, not the core molecular function. Supporting Evidence: PMID:12370307 Disruption of the NFATc1 gene resulted in embryonic lethality due to aberrant heart valve formation and cardiac insufficiency file:human/NFATC1/NFATC1-deep-research-falcon.md Genetic loss in mice causes embryonic lethality associated with cardiovascular defects and organ hypoplasia, indicating a nonredundant developmental role |
| GO:0003184 pulmonary valve morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: pulmonary valve morphogenesis. Reason: As for aortic valve morphogenesis: pleiotropic developmental role supported by mouse knockout of Nfatc1 (defective semilunar valves). Supporting Evidence: PMID:12370307 Disruption of the NFATc1 gene resulted in embryonic lethality due to aberrant heart valve formation and cardiac insufficiency |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based IEA: DNA binding. Reason: Correct but general; the more precise sequence-specific Pol II cis-regulatory DNA binding terms are also annotated. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA: DNA-binding transcription factor activity. Reason: Correct, if less specific than the Pol II-specific term. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:10821850 Divergent hTAFII31-binding motifs hidden in activation domai... | ACCEPT | Summary: TAS citing a study of hTAFII31-binding motifs in acidic activation domains. Reason: The activity (DNA-binding transcription factor) is certainly correct for NFATC1. The cited abstract names 'NFAT1', which in the common nomenclature denotes NFATC2 rather than NFATC1, so the reference is weak support for NFATC1 specifically; the annotation is nevertheless correct and is independently supported (PMID:9506523, PMID:8202141). Supporting Evidence: PMID:10821850 identification of hTAF(II)31-binding sequences that are critical for the activity of the activation domains of five human transcription factors: NFAT1, ALL1, NF-IL6, ESX, and HSF-1 PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:9506523 Solution structure of the core NFATC1/DNA complex. | ACCEPT | Summary: TAS citing the NMR solution structure of the human NFATC1 DNA-binding domain bound to the IL2 ARRE2 site. Reason: Directly supports sequence-specific DNA binding by the NFATC1 Rel homology region at a Pol II promoter element. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0005515 protein binding | IPI PMID:17882263 Requirement for O-linked N-acetylglucosaminyltransferase in ... | REMOVE | Summary: IPI with OGT (O-GlcNAc transferase) in lymphocytes. Reason: Bare protein binding is uninformative. The finding is that NFATC1 is an O-GlcNAc-modified substrate of OGT; no informative molecular function of NFATC1 follows from being a glycosylation substrate. The interaction itself is not disputed. Supporting Evidence: PMID:17882263 This experiment showed interaction of OGT to NFΞΊB and NFATc1 |
| GO:0005515 protein binding | IPI PMID:18218901 NFAT binding and regulation of T cell activation by the cyto... | REMOVE | Summary: IPI with HOMER2 (Homer scaffold proteins bind NFAT and compete with calcineurin). Reason: Bare protein binding is uninformative. Homer binding is a regulatory interaction in which NFATC1 is the bound client; no specific GO molecular function term captures an informative activity of NFATC1 here. The interaction is not disputed. Supporting Evidence: PMID:18218901 purified GST-Homer2 and GST-Homer3 fusion proteins could pull down NFATc1, c2, and c4 isoforms expressed in human embryonic kidney (HEK) cells |
| GO:0005515 protein binding | IPI PMID:18218901 NFAT binding and regulation of T cell activation by the cyto... | REMOVE | Summary: IPI with HOMER3. Reason: Bare protein binding is uninformative; as for HOMER2, NFATC1 is the regulated client of the Homer scaffold. Supporting Evidence: PMID:18218901 purified GST-Homer2 and GST-Homer3 fusion proteins could pull down NFATc1, c2, and c4 isoforms expressed in human embryonic kidney (HEK) cells |
| GO:0005515 protein binding | IPI PMID:21880741 Nuclear factor of activated T cells (NFAT) proteins repress ... | REMOVE | Summary: IPI with DVL1 (Dishevelled), underlying NFAT-mediated repression of canonical Wnt signaling. Reason: Bare protein binding is uninformative. The functional consequence (negative regulation of Wnt signaling) is captured separately (GO:0030178, kept as non-core); the interaction itself is not disputed. Supporting Evidence: PMID:21880741 hNFATc1 and mNFATc1 were co-immunoprecipitated with Dvl as well as mNFATc4 |
| GO:0005515 protein binding | IPI PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | MODIFY | Summary: IPI with PPP3CA (calcineurin catalytic subunit); structural study of calcineurin substrate engagement using the NFATc1 LxVP docking motif. Reason: Replace bare protein binding with protein phosphatase 2B binding: NFATC1 docks on calcineurin through its PxIxIT and LxVP motifs, which is the informative activity and is already annotated from PMID:10860980. Proposed replacements: protein phosphatase 2B binding Supporting Evidence: PMID:23468591 we showed that excess amounts of a peptide that encodes the LxVP docking motif from NFATc1, but not a mutant (LxVPc1mut LAVPβAAAA) also disrupted A238L-CN binding |
| GO:0005515 protein binding | IPI PMID:24954618 The LxVP and PxIxIT NFAT motifs bind jointly to overlapping ... | MODIFY | Summary: IPI with PPP3CA; NMR mapping of the NFATc1 LxVP peptide binding site on the calcineurin catalytic subunit. Reason: Replace bare protein binding with protein phosphatase 2B binding (calcineurin docking via LxVP/PxIxIT motifs). Proposed replacements: protein phosphatase 2B binding Supporting Evidence: PMID:24954618 Here, we present evidence that a 15-mer peptide from NFATc1 containing the conserved LxVP sequence binds to a CnA region overlapping with the PxIxIT-binding epitope. |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: IPI with JUN from tandem-affinity purification of transcription factor complexes, confirmed by Western blot in the chromatin fraction. Reason: Replace bare protein binding with RNA polymerase II-specific DNA-binding transcription factor binding. Cooperative binding with AP-1 (FOS/JUN) at composite NFAT:AP-1 sites is the defining mode of NFAT action. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction file:human/NFATC1/NFATC1-deep-research-falcon.md Because monomeric NFATβDNA binding is weak, productive transcriptional regulation depends on cooperative interactions with other transcription factors |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: IPI with ATF2 (TAP/MS, Western-confirmed in chromatin fraction). Reason: Replace bare protein binding with RNA polymerase II-specific DNA-binding transcription factor binding; ATF2 is a bZIP transcription factor partner of NFATC1 on chromatin. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: IPI with CREB1 (TAP/MS and reciprocal TAP/MS, Western-confirmed). Reason: Replace bare protein binding with RNA polymerase II-specific DNA-binding transcription factor binding. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction PMID:25609649 Our TAP/MS and corresponding reciprocal TAP/MS analysis showed that CREB1 and NFATC1/2 bind to each other only in the chromatin fraction, which is also the case for ATF1/2/3/7 and NFATC1 |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: IPI with ATF1 (TAP/MS, Western-confirmed). Reason: Replace bare protein binding with RNA polymerase II-specific DNA-binding transcription factor binding. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: IPI with ATF3 (TAP/MS and reciprocal purification). Reason: Replace bare protein binding with RNA polymerase II-specific DNA-binding transcription factor binding; the reciprocal purification supports an NFATC1-ATF3 association on chromatin. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:25609649 Our TAP/MS and corresponding reciprocal TAP/MS analysis showed that CREB1 and NFATC1/2 bind to each other only in the chromatin fraction, which is also the case for ATF1/2/3/7 and NFATC1 |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | REMOVE | Summary: IPI with HOXC13 from high-throughput TAP/MS of transcription factor complexes. Reason: Bare protein binding is uninformative, and the HOX association comes only from the proteomic screen without the Western or functional follow-up given to the bZIP partners; no informative function can be assigned from it. Supporting Evidence: PMID:25609649 NFATC1-associated protein JUN, HOXD13, CREB1, ATF1, ATF3 |
| GO:0005528 FK506 binding | TAS PMID:8702849 Characterization of a new isoform of the NFAT (nuclear facto... | REMOVE | Summary: TAS: FK506 binding, citing characterization of the NFATc.beta isoform. Reason: NFATC1 does not bind FK506. FK506 binds FKBP12 (FKBP1A), and the FKBP12-FK506 complex inhibits calcineurin, which is why NFAT activation is FK506/CsA-sensitive. The cited paper shows only that NFATc.beta activity is CsA-sensitive, which reflects calcineurin dependence, not drug binding by NFATC1. Supporting Evidence: PMID:8702849 Transient expression of NFATc.beta was capable of activating an interleukin-2 NFAT-driven reporter gene in stimulated Jurkat cells in a CsA-sensitive manner. |
| GO:0005634 nucleus | EXP PMID:16511445 A genome-wide Drosophila RNAi screen identifies DYRK-family ... | ACCEPT | Summary: EXP: nucleus (NFAT proteins translocate to the nucleus after calcineurin dephosphorylation). Reason: Nucleus is where NFATC1 performs its transcription factor function. The cached abstract discusses NFAT1, but the curator read the full text and the localization is correct for NFATC1. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: nucleus. Reason: Correct; site of the core transcriptional activity. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005634 nucleus | IDA PMID:12370307 Targeted disruption of NFATc3, but not NFATc4, reveals an in... | ACCEPT | Summary: IDA: nucleus, from a study of NFAT isoforms in heart (NFATc1 detected in heart nuclear-extract EMSA supershifts). Reason: Nuclear NFATc1 was detected by antibody supershift in heart nuclear extracts; nuclear localization is correct for NFATC1. Supporting Evidence: PMID:12370307 In analyses with selected antibodies, the data demonstrate the presence of NFATc1 (lane 7), NFATc2 (lanes 8 and 9), NFATc3 (lanes 10 and 12), and NFATc4 (lane 13) in the heart |
| GO:0005634 nucleus | IDA PMID:15304486 Essential role of p38 mitogen-activated protein kinase in ca... | ACCEPT | Summary: IDA: nucleus of RANKL-stimulated osteoclasts. Reason: RANKL induces nuclear accumulation of NFATc1 in osteoclasts; correct location for its function. Supporting Evidence: PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA: nucleus. Reason: Correct. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: IDA (Human Protein Atlas immunofluorescence): nucleoplasm. Reason: Consistent with a nuclear transcription factor. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2730867 | ACCEPT | Summary: Reactome TAS: nucleoplasm (translocation of CaN:CaM:NFAT to nucleus). Reason: Correct location of activated NFATC1. Supporting Evidence: Reactome:R-HSA-2730867 Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g. IL2). |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4551465 | ACCEPT | Summary: Reactome TAS: nucleoplasm (translocation of NFATC1:CaN:CaM to nucleus). Reason: Correct location of activated NFATC1. Supporting Evidence: Reactome:R-HSA-2730867 Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g. IL2). |
| GO:0005667 transcription regulator complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: part of transcription regulator complex. Reason: NFATC1 acts in cooperative DNA-bound complexes with AP-1 and other bZIP factors (and PU.1, GATA4, MEF2 in other contexts); the complex-membership annotation is appropriate. Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. |
| GO:0005737 cytoplasm | EXP PMID:16511445 A genome-wide Drosophila RNAi screen identifies DYRK-family ... | ACCEPT | Summary: EXP: cytoplasm (phosphorylated inactive NFAT resides in the cytoplasm). Reason: Correct: the phosphorylated, inactive pool of NFATC1 is cytoplasmic, and cytoplasmic retention is central to its regulation. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA: cytoplasm. Reason: Correct (resting-state location). Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: cytoplasm. Reason: Correct (resting-state location). Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005737 cytoplasm | TAS PMID:8202141 NF-AT components define a family of transcription factors ta... | ACCEPT | Summary: TAS: cytoplasm, citing the original purification of NF-ATc as the cytosolic component of NF-AT. Reason: NF-ATc was named as the cytosolic component of the NF-AT complex; correct. Supporting Evidence: PMID:8202141 Here we purify two proteins encoded by separate genes that represent the pre-existing (p) and cytosolic (c) components of NF-AT. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2025890 | ACCEPT | Summary: Reactome TAS: cytosol (Reactome:R-HSA-2025890; calcineurin binding/dephosphorylation of NFAT in the cytosol prior to nuclear import). Reason: Correct: calcineurin docks on and dephosphorylates cytosolic NFATC1 before its nuclear import. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730849 | ACCEPT | Summary: Reactome TAS: cytosol (Reactome:R-HSA-2730849; calcineurin binding/dephosphorylation of NFAT in the cytosol prior to nuclear import). Reason: Correct: calcineurin docks on and dephosphorylates cytosolic NFATC1 before its nuclear import. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730867 | ACCEPT | Summary: Reactome TAS: cytosol (Reactome:R-HSA-2730867; calcineurin binding/dephosphorylation of NFAT in the cytosol prior to nuclear import). Reason: Correct: calcineurin docks on and dephosphorylates cytosolic NFATC1 before its nuclear import. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551451 | ACCEPT | Summary: Reactome TAS: cytosol (Reactome:R-HSA-4551451; calcineurin binding/dephosphorylation of NFAT in the cytosol prior to nuclear import). Reason: Correct: calcineurin docks on and dephosphorylates cytosolic NFATC1 before its nuclear import. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551465 | ACCEPT | Summary: Reactome TAS: cytosol (Reactome:R-HSA-4551465; calcineurin binding/dephosphorylation of NFAT in the cytosol prior to nuclear import). Reason: Correct: calcineurin docks on and dephosphorylates cytosolic NFATC1 before its nuclear import. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro IEA: regulation of DNA-templated transcription. Reason: Correct but general; more specific positive regulation of Pol II transcription terms are also annotated. Supporting Evidence: PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: IDA (Human Protein Atlas): nuclear body. Reason: Single antibody-based localization without functional follow-up; compatible with nuclear localization but not a defining location. |
| GO:0030178 negative regulation of Wnt signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from chicken NFATC1: negative regulation of Wnt signaling pathway (NFAT-Dvl interaction represses canonical Wnt signaling). Reason: NFATc1 binds Dvl and represses beta-catenin-dependent signaling in the neural tube; human and mouse NFATc1 co-immunoprecipitate with Dvl. Plausible but context-specific, not a core function. Supporting Evidence: PMID:21880741 hNFATc1 and mNFATc1 were co-immunoprecipitated with Dvl as well as mNFATc4 |
| GO:0030346 protein phosphatase 2B binding | EXP PMID:10860980 A second calcineurin binding site on the NFAT regulatory dom... | ACCEPT | Summary: EXP: protein phosphatase 2B binding; identification of a second calcineurin-binding site in human NFATc. Reason: NFATC1 docks calcineurin through two motifs (PxIxIT/CnBP-A and LxVP/CnBP-B); this docking activity is the mechanism that makes NFATC1 a calcineurin substrate and couples Ca2+ to its nuclear import. Supporting Evidence: PMID:10860980 Here we report the identification of a second Cn-binding element in NFATc, which synergizes with the previously identified element. |
| GO:0030346 protein phosphatase 2B binding | IPI PMID:10860980 A second calcineurin binding site on the NFAT regulatory dom... | ACCEPT | Summary: IPI with calmodulin/calcineurin (PPP3CA): protein phosphatase 2B binding. Reason: Same finding; calcineurin docking by the NFATc regulatory domain. Supporting Evidence: PMID:10860980 Here we report the identification of a second Cn-binding element in NFATc, which synergizes with the previously identified element. |
| GO:0033173 calcineurin-NFAT signaling cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: calcineurin-NFAT signaling cascade. Reason: Core process. NFATC1 is the effector transcription factor of the cascade: its calcineurin-dependent dephosphorylation and nuclear import convert Ca2+ signals into gene expression. Supporting Evidence: PMID:16511445 In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. PMID:14979875 MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:14979875 Co-operative interactions between NFAT (nuclear factor of ac... | ACCEPT | Summary: IDA: calcineurin-NFAT signaling cascade (ionophore-activated calcineurin drives NFATc1-dependent MT1-MMP transcription; CsA blocks it). Reason: Supported by the abstract: calcineurin activation increases NFATc1 nuclear DNA-binding activity and target transcription, suppressed by cyclosporin A. Supporting Evidence: PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. PMID:14979875 MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. |
| GO:0035556 intracellular signal transduction | IDA PMID:14749367 Regulation of apoptosis by the Ft1 protein, a new modulator ... | KEEP AS NON CORE | Summary: IDA (acts upstream of or within): intracellular signal transduction via a PDK1/PKB/GSK3/NF-ATc cascade controlling Fas ligand production. Reason: NFATc is the transcriptional endpoint of the PKB/GSK3 cascade described; 'intracellular signal transduction' is very general, and the calcineurin-NFAT signaling cascade term better captures NFATC1's signaling role. Abstract-only; kept as non-core rather than overruling the curator. Supporting Evidence: PMID:14749367 We demonstrate that this phenomenon occurs via a PDK1/PKB/GSK3/NF-ATc signaling cascade that controls the production of the proapoptotic hormone Fas ligand. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:14749367 Regulation of apoptosis by the Ft1 protein, a new modulator ... | ACCEPT | Summary: IDA (acts upstream of or within): positive regulation of DNA-templated transcription (Fas ligand). Reason: NFATC1 is a transcriptional activator; the general term is correct. Supporting Evidence: PMID:14749367 We demonstrate that this phenomenon occurs via a PDK1/PKB/GSK3/NF-ATc signaling cascade that controls the production of the proapoptotic hormone Fas ligand. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:14979875 Co-operative interactions between NFAT (nuclear factor of ac... | ACCEPT | Summary: IDA: positive regulation of DNA-templated transcription (MT1-MMP). Reason: Correct; NFATc1 transactivates MT1-MMP and binds its promoter in vivo. Supporting Evidence: PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. PMID:14979875 Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: positive regulation of transcription by RNA polymerase II. Reason: Core process for NFATC1 as a Pol II transcriptional activator. Supporting Evidence: PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:14979875 Co-operative interactions between NFAT (nuclear factor of ac... | ACCEPT | Summary: IDA: positive regulation of transcription by RNA polymerase II (MT1-MMP promoter). Reason: Directly supported. Supporting Evidence: PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. PMID:14979875 Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:14979875 Co-operative interactions between NFAT (nuclear factor of ac... | ACCEPT | Summary: IGI with SP1: cooperative activation of MT1-MMP transcription. Reason: Additive/cooperative transactivation by NFATc1 and Sp1 at the MT1-MMP promoter; supports positive regulation of Pol II transcription. Supporting Evidence: PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:14979875 Co-operative interactions between NFAT (nuclear factor of ac... | ACCEPT | Summary: IGI with EGR1: cooperative activation of MT1-MMP transcription. Reason: As for Sp1; Egr-1 acts at the overlapping Sp1/Egr-1 site. Supporting Evidence: PMID:14979875 Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: positive regulation of transcription by RNA polymerase II. Reason: Correct. Supporting Evidence: PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression |
| GO:0048273 mitogen-activated protein kinase p38 binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: mitogen-activated protein kinase p38 binding. Reason: p38 MAPK phosphorylates NFATc1 in RANKL-stimulated osteoclast precursors; NFATC1 is the kinase substrate, so binding p38 is a regulatory interaction rather than a core activity. Kept as non-core rather than removed as it is a specific, biologically supported interaction term. Supporting Evidence: PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. |
| GO:0050728 negative regulation of inflammatory response | IDA PMID:35930205 CD69-oxLDL ligand engagement induces Programmed Cell Death 1... | MARK AS OVER ANNOTATED | Summary: IDA: negative regulation of inflammatory response (oxLDL-CD69 engagement induces PD-1 via NFAT in human T cells). Reason: The full text shows CD69-driven PD-1 induction that is blocked by cyclosporin A, i.e. NFAT-family (calcineurin) dependence; the NFAT inhibition was pharmacological and not NFATC1-specific, and the anti-inflammatory outcome is an inference about downstream PD-1 function rather than a process NFATC1 was shown to execute. The direct activity is transcriptional activation of PDCD1. Supporting Evidence: PMID:35930205 Here, we report that the binding of oxLDL to CD69 induces the expression of PD-1 through the activation of nuclear factor of activated T cells 1 (NFAT) in human T cells. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: RNA polymerase II-specific DNA-binding transcription factor binding. Reason: Cooperative binding with partner transcription factors (AP-1 FOS/JUN, bZIP ATF/CREB factors, PU.1, GATA4, MEF2) is intrinsic to NFAT function, since monomeric NFAT-DNA binding is weak. Supporting Evidence: PMID:25609649 Western analysis confirmed that NFATC1 binds to JUN, CREB1 and ATF1/2 predominantly in the chromatin fraction PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. file:human/NFATC1/NFATC1-deep-research-falcon.md Because monomeric NFATβDNA binding is weak, productive transcriptional regulation depends on cooperative interactions with other transcription factors |
| GO:1905064 negative regulation of vascular associated smooth muscle cell differentiation | IDA PMID:23853098 MicroRNA-124 suppresses the transactivation of nuclear facto... | KEEP AS NON CORE | Summary: IDA: negative regulation of vascular associated smooth muscle cell differentiation (miR-124 targets NFATc1 and promotes a contractile phenotype in pulmonary artery smooth muscle cells). Reason: The study shows that miR-124 suppresses NFATc1 expression and NFAT nuclear translocation and promotes the contractile (differentiated) phenotype; NFATc1, as the transcription factor, plausibly drives the synthetic phenotype. Context-specific and pleiotropic, so non-core. Supporting Evidence: PMID:23853098 However, miR-124 overexpression caused nearly complete retention of AcGFP-NFATc1 in the cytoplasm despite stimulation with ionomycin/PMA PMID:23853098 we propose that miR-124 may play a role in promoting a contractile, differentiated phenotype in PASMC by inhibiting the NFAT pathway |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: IDA: sequence-specific double-stranded DNA binding (methyl-SELEX/HT-SELEX profiling of human transcription factors). Reason: Core DNA-binding activity; NFAT binding to CGGAA-containing motifs is positively influenced by CpG methylation in this dataset. Supporting Evidence: PMID:28473536 some motifs containing a CGGAA subsequence, can be bound by TFs that are either negatively (ETS) or positively (NFAT) influenced by methylation PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA IEA: sequence-specific double-stranded DNA binding. Reason: Correct. Supporting Evidence: PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
| GO:0030316 osteoclast differentiation | IMP PMID:12479813 Induction and activation of the transcription factor NFATc1 ... | NEW | Summary: Proposed NEW: NFATC1 is the master transcription factor of osteoclast terminal differentiation downstream of RANKL (mouse evidence, orthologous function). Reason: Participation test: NFATC1 does the transcriptional work of the osteoclast differentiation program (it is induced by RANKL, activated by calcineurin, and directly activates osteoclast genes such as cathepsin K with PU.1 and MITF); it is not merely necessary, since ectopic NFATc1 drives differentiation without RANKL. Comparator: the partner lineage transcription factor SPI1 (PU.1) carries osteoclast differentiation (GO:0030316) in human GOA, so transcription factors that execute the program are conventionally annotated to it. Evidence is from mouse cells; the human gene is orthologous and the pathway conserved. Supporting Evidence: PMID:12479813 NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling PMID:12479813 NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL PMID:15304486 RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. |
| GO:0032743 positive regulation of interleukin-2 production | IMP PMID:8202141 NF-AT components define a family of transcription factors ta... | NEW | Summary: Proposed NEW: NF-ATc (NFATC1) activates the IL2 promoter and a dominant-negative NF-ATc blocks IL2 promoter activation in T cells. Reason: NFATC1 directly binds the IL2 ARRE2 element and transactivates the IL2 promoter; it therefore does the transcriptional work of positively regulating IL-2 production (regulation by a transcription factor of its target cytokine gene), not merely being required upstream. This is the canonical T cell output of the NFAT pathway. Supporting Evidence: PMID:8202141 Expression of the full-length complementary DNA encoding NF-ATc activates the interleukin (IL-2) promoter in non-T lymphocytes PMID:8202141 indicating that NF-ATc is required for IL-2 gene expression PMID:9506523 Here we report the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the ARRE2 DNA site from the interleukin-2 promoter. |
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Download this section (compressed HTML)Q: Which NFATC1 isoforms (P1-driven inducible alpha-A versus P2-driven constitutive beta/B/C forms) carry the osteoclast, valve and T cell programs, and do the C-terminal TAD-B-containing long isoforms have distinct target sets?
Q: Should cooperative NFAT:AP-1 complexes on composite elements be represented in GO-CAM as NFATC1 activator activity with has_input/part_of links to the FOS/JUN activities, rather than via binding terms?
Q: Is the reported NFATC1-Dvl interaction and Wnt repression relevant in mammalian tissues, or restricted to the chick neural tube context in which it was characterized?
Q: Does NFATC1 directly repress replication-dependent histone genes in non-transformed human cells (as reported in MCF7 cells, PMID:38926604), and if so does it act as a sequence-specific repressor that would warrant negative regulation of transcription by RNA polymerase II (GO:0000122)?
Q: In chronically stimulated CD8+ T cells, which survival and exhaustion genes (e.g. TOX, BCL2L11/BCL2) are direct NFATC1/alphaA targets, and is this program AP-1 independent as proposed for NFAT-driven exhaustion?
Experiment: Isoform-specific knockout or degron alleles of human NFATC1 in primary T cells and iPSC-derived osteoclasts, followed by CUT&RUN and RNA-seq, to separate direct targets of the inducible short isoform from the long isoforms.
Experiment: Genome-wide NFATC1 and JUN/FOS co-occupancy mapping with AP-1-binding-deficient NFATC1 mutants to quantify which NFATC1 target genes require cooperative AP-1 binding.
Experiment: NFATC1 knockout or degron in non-transformed human cells (e.g. primary endothelial cells or T cells) with calcineurin inhibitor and ionomycin controls, followed by CUT&RUN and nascent RNA profiling of the histone gene clusters, to test whether NFATC1 directly represses histone transcription.
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