NFAC3_MOUSE
ID NFAC3_MOUSE Reviewed; 1075 AA.
AC P97305; Q60896;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Nuclear factor of activated T-cells, cytoplasmic 3;
DE Short=NF-ATc3;
DE Short=NFATc3;
DE AltName: Full=NFATx;
DE AltName: Full=T-cell transcription factor NFAT4;
DE Short=NF-AT4;
GN Name=Nfatc3; Synonyms=Nfat4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM X1).
RC TISSUE=Thymus;
RX PubMed=7650004; DOI=10.1074/jbc.270.34.19898;
RA Ho S.N., Thomas D.J., Timmerman L.A., Li X., Francke U., Crabtree G.R.;
RT "NFATc3, a lymphoid-specific NFATc family member that is calcium-regulated
RT and exhibits distinct DNA binding specificity.";
RL J. Biol. Chem. 270:19898-19907(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12-1075 (ISOFORMS X1; X2 AND DELTA-X).
RC TISSUE=Thymic lymphoma;
RX PubMed=9017603; DOI=10.1091/mbc.8.1.157;
RA Liu J., Koyano-Nakagawa N., Amasaki Y., Saito-Ohara F., Ikeuchi T.,
RA Imai S., Takano T., Arai N., Yokota T., Arai K.;
RT "Calcineurin-dependent nuclear translocation of a murine transcription
RT factor NFATx: molecular cloning and functional characterization.";
RL Mol. Biol. Cell 8:157-170(1997).
RN [3]
RP REVIEW.
RX PubMed=10089876; DOI=10.1016/s0092-8674(00)80571-1;
RA Crabtree G.R.;
RT "Generic signals and specific outcomes: signaling through Ca2+,
RT calcineurin, and NF-AT.";
RL Cell 96:611-614(1999).
RN [4]
RP DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=12370307; DOI=10.1128/mcb.22.21.7603-7613.2002;
RA Wilkins B.J., De Windt L.J., Bueno O.F., Braz J.C., Glascock B.J.,
RA Kimball T.F., Molkentin J.D.;
RT "Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect
RT in calcineurin-mediated cardiac hypertrophic growth.";
RL Mol. Cell. Biol. 22:7603-7613(2002).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=12750314; DOI=10.1161/01.res.0000077045.84609.9f;
RA Bushdid P.B., Osinska H., Waclaw R.R., Molkentin J.D., Yutzey K.E.;
RT "NFATc3 and NFATc4 are required for cardiac development and mitochondrial
RT function.";
RL Circ. Res. 92:1305-1313(2003).
RN [6]
RP DEVELOPMENTAL STAGE.
RX PubMed=17198697; DOI=10.1016/j.ydbio.2006.11.036;
RA Yang X.Y., Yang T.T.C., Schubert W., Factor S.M., Chow C.-W.;
RT "Dosage-dependent transcriptional regulation by the calcineurin/NFAT
RT signaling in developing myocardium transition.";
RL Dev. Biol. 303:825-837(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-344, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP INTERACTION WITH TRIM17, AND SUBCELLULAR LOCATION.
RX PubMed=25215946; DOI=10.1038/cdd.2014.141;
RA Mojsa B., Mora S., Bossowski J.P., Lassot I., Desagher S.;
RT "Control of neuronal apoptosis by reciprocal regulation of NFATc3 and
RT Trim17.";
RL Cell Death Differ. 22:274-286(2015).
CC -!- FUNCTION: Acts as a regulator of transcriptional activation. Plays a
CC role in the inducible expression of cytokine genes in T-cells,
CC especially in the induction of the IL-2 (By similarity). Along with
CC NFATC4, involved in embryonic heart development (PubMed:12750314).
CC {ECO:0000250|UniProtKB:Q12968, ECO:0000269|PubMed:12750314}.
CC -!- SUBUNIT: Member of the multicomponent NFATC transcription complex that
CC consists of at least two components, a pre-existing cytoplasmic
CC component NFATC2 and an inducible nuclear component NFATC1. Other
CC members such as NFATC4, or members of the activating protein-1 family,
CC MAF, GATA4 and Cbp/p300 can also bind the complex. NFATC proteins bind
CC to DNA as monomers. Interacts with TRIM17; this interaction prevents
CC NFATC3 nuclear localization (PubMed:25215946).
CC {ECO:0000269|PubMed:25215946}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269|PubMed:25215946}.
CC Note=Cytoplasmic for the phosphorylated form and nuclear after
CC activation that is controlled by calcineurin-mediated
CC dephosphorylation. Rapid nuclear exit of NFATC is thought to be one
CC mechanism by which cells distinguish between sustained and transient
CC calcium signals. The subcellular localization of NFATC plays a key role
CC in the regulation of gene transcription.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=X1;
CC IsoId=P97305-1; Sequence=Displayed;
CC Name=X2;
CC IsoId=P97305-2; Sequence=VSP_005604;
CC Name=Delta-X;
CC IsoId=P97305-3; Sequence=VSP_005603;
CC -!- TISSUE SPECIFICITY: Expressed in thymus. Weakly expressed in muscle,
CC spleen and kidney. Also expressed in lymph node. Expressed in the heart
CC (PubMed:12370307). {ECO:0000269|PubMed:12370307}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the developing heart at 13.5 and 16.5
CC dpc, during the transition from spongy to compact myocardium.
CC {ECO:0000269|PubMed:17198697}.
CC -!- DOMAIN: Rel Similarity Domain (RSD) allows DNA-binding and cooperative
CC interactions with AP1 factors. {ECO:0000250}.
CC -!- PTM: Phosphorylated by NFATC-kinase; dephosphorylated by calcineurin.
CC {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: At 10.5 dpc, knockout embryo exhibit normal heart
CC development (PubMed:12750314). Adults show attenuated phenotype during
CC calcineurin-induced cardiac hypertrophy compared to wild-type
CC littermates (PubMed:12370307). Simultaneous knockout of NFATC3 and
CC NFATC4 results in embryonic death soon after 10.5 dpc. Embryos appear
CC normal at 9.5 dpc. At 10.5 dpc, they exhibit defects in cardiac
CC development, including dilated thin translucent hearts, pericardial
CC effusion and anemia. Despite a mild generalized developmental delay,
CC the heads, tails, and limb buds are well developed. By 11.5 dpc, mutant
CC embryos are either necrotic or resorbed (PubMed:12750314).
CC {ECO:0000269|PubMed:12370307, ECO:0000269|PubMed:12750314}.
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DR EMBL; D85612; BAA12833.1; -; mRNA.
DR EMBL; U28807; AAA93249.1; -; mRNA.
DR AlphaFoldDB; P97305; -.
DR SMR; P97305; -.
DR IntAct; P97305; 1.
DR STRING; 10090.ENSMUSP00000104931; -.
DR iPTMnet; P97305; -.
DR PhosphoSitePlus; P97305; -.
DR EPD; P97305; -.
DR jPOST; P97305; -.
DR MaxQB; P97305; -.
DR PaxDb; P97305; -.
DR PRIDE; P97305; -.
DR ProteomicsDB; 252955; -. [P97305-1]
DR ProteomicsDB; 252956; -. [P97305-2]
DR ProteomicsDB; 252957; -. [P97305-3]
DR MGI; MGI:103296; Nfatc3.
DR eggNOG; ENOG502QWQ4; Eukaryota.
DR InParanoid; P97305; -.
DR PhylomeDB; P97305; -.
DR Reactome; R-MMU-2025928; Calcineurin activates NFAT.
DR Reactome; R-MMU-2871809; FCERI mediated Ca+2 mobilization.
DR Reactome; R-MMU-5607763; CLEC7A (Dectin-1) induces NFAT activation.
DR ChiTaRS; Nfatc3; mouse.
DR PRO; PR:P97305; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; P97305; protein.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:MGI.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0001974; P:blood vessel remodeling; IMP:MGI.
DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IGI:MGI.
DR GO; GO:0033173; P:calcineurin-NFAT signaling cascade; IGI:MGI.
DR GO; GO:0014898; P:cardiac muscle hypertrophy in response to stress; IGI:MGI.
DR GO; GO:0045333; P:cellular respiration; IMP:MGI.
DR GO; GO:0071277; P:cellular response to calcium ion; IDA:MGI.
DR GO; GO:0071285; P:cellular response to lithium ion; IDA:MGI.
DR GO; GO:0007507; P:heart development; IGI:MGI.
DR GO; GO:0014904; P:myotube cell development; IMP:MGI.
DR GO; GO:0014902; P:myotube differentiation; IMP:MGI.
DR GO; GO:1902894; P:negative regulation of miRNA transcription; ISO:MGI.
DR GO; GO:1905064; P:negative regulation of vascular associated smooth muscle cell differentiation; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:2001256; P:regulation of store-operated calcium entry; IMP:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0001666; P:response to hypoxia; IDA:MGI.
DR GO; GO:0048741; P:skeletal muscle fiber development; IMP:MGI.
DR GO; GO:0030217; P:T cell differentiation; IMP:MGI.
DR GO; GO:0048538; P:thymus development; IMP:MGI.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0097084; P:vascular associated smooth muscle cell development; IGI:MGI.
DR GO; GO:0035886; P:vascular associated smooth muscle cell differentiation; IGI:MGI.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 2.60.40.340; -; 1.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR002909; IPT_dom.
DR InterPro; IPR008366; NFAT.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR032397; RHD_dimer.
DR InterPro; IPR011539; RHD_DNA_bind_dom.
DR InterPro; IPR037059; RHD_DNA_bind_dom_sf.
DR PANTHER; PTHR12533; PTHR12533; 1.
DR Pfam; PF16179; RHD_dimer; 1.
DR Pfam; PF00554; RHD_DNA_bind; 1.
DR PRINTS; PR01789; NUCFACTORATC.
DR SMART; SM00429; IPT; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
DR PROSITE; PS50254; REL_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Alternative splicing; Cytoplasm;
KW Developmental protein; DNA-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; Transcription; Transcription regulation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q12968"
FT CHAIN 2..1075
FT /note="Nuclear factor of activated T-cells, cytoplasmic 3"
FT /id="PRO_0000205181"
FT REPEAT 207..223
FT /note="1"
FT REPEAT 236..252
FT /note="2"
FT REPEAT 292..308
FT /note="3"
FT DOMAIN 415..596
FT /note="RHD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00265"
FT DNA_BIND 444..451
FT /evidence="ECO:0000250"
FT REGION 18..37
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 109..114
FT /note="Calcineurin-binding"
FT REGION 205..305
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 207..308
FT /note="3 X SP repeats"
FT REGION 358..389
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 700..742
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 862..886
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 898..986
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1056..1075
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 273..275
FT /note="Nuclear localization signal"
FT MOTIF 686..688
FT /note="Nuclear localization signal"
FT MOTIF 1031..1040
FT /note="Nuclear export signal"
FT COMPBIAS 227..272
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 361..375
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 898..942
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 949..986
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylthreonine"
FT /evidence="ECO:0000250|UniProtKB:Q12968"
FT MOD_RES 344
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 372
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12968"
FT MOD_RES 1065
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12968"
FT VAR_SEQ 468..497
FT /note="Missing (in isoform Delta-X)"
FT /evidence="ECO:0000303|PubMed:9017603"
FT /id="VSP_005603"
FT VAR_SEQ 1035..1075
FT /note="VNEIIGRDMSQISVSQATEVMRDTPLPGPASPDLMTSHSAH -> DQLISDL
FT EHQPSGSTEKWSNHSEFSCPVPFWRI (in isoform X2)"
FT /evidence="ECO:0000303|PubMed:9017603"
FT /id="VSP_005604"
FT CONFLICT 12..34
FT /note="LDFKLVFGEDGAPAPPPPGSRPA -> PRRVLFSVSAQLPSRTRPGPSDL
FT (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 57..61
FT /note="TTPLC -> NSSLG (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 68
FT /note="P -> LQ (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 82..83
FT /note="SH -> GY (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 90..93
FT /note="CEIP -> GDIS (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 113
FT /note="F -> I (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 121..124
FT /note="QQEL -> HQGT (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 132
FT /note="Q -> H (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 140
FT /note="F -> Y (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 641
FT /note="G -> R (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 646
FT /note="V -> A (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 707..734
FT /note="REDTDLPSVPSLPVPHSAQAQRPSSETG -> KEKTQICLQFHLCLCLILPS
FT PEALLRDR (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 746
FT /note="G -> S (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
FT CONFLICT 1075
FT /note="H -> Q (in Ref. 2; AAA93249)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1075 AA; 115451 MW; 4ED38C9AA6F452BB CRC64;
MTTANCGAHD ELDFKLVFGE DGAPAPPPPG SRPADLEPDD CASIYIFNVD PPPSTLTTPL
CLPHHGLPSH SSVLSPSFQL QSHKNYEGTC EIPESKYSPL GGPKPFECPS IQFTSISPNC
QQELDAHEDD LQINDPEREF LERPSRDHLY LPLEPSYRES SLSPSPASSI SSRSWFSDAS
SCESLSHIYD DVDSELNEAA ARFTLGSPLT SPGGSPGGCP GEESWHQQYG SGHSLSPRQS
PCHSPRSSIT DENWLSPRPA SGPSSRPTSP CGKRRHSSAE VCYAGSLSPH HSPVPSPGHS
PRGSVTEDTW LTAPVHTGSG LSPAPFPFQY CVETDIPLKT RKTSEDQAAI LPGKLEICSD
DQGNLSPSRE TSVDDGLGSQ YPLKKDSSGD QFLSVPSPFT WSKPKPGHTP IFRTSSLPPL
DWPLPTHFGQ CELKIEVQPK THHRAHYETE GSRGAVKAST GGHPVVKLLG YSEKPINLQM
FIGTADDRYL RPHAFYQVHR ITGKTVATAS QEIIIASTKV LEIPLLPENN MSASIDCAGI
LKLRNSDIEL RKGETDIGRK NTRVRLVFRV HIPQPSGKVL SLQIASIPVE CSQRSAQELP
HIEKYSINSC SVNGGHEMIV TGSNFLPESK IIFLEKGQDG GPHWEVEGKI IREKCQGAHI
VLEVPPYHNP AVTSAVQVHF YLCNGKRKKS QSQRFTYTPV LMKQEQREDT DLPSVPSLPV
PHSAQAQRPS SETGHPHDRA MSAPGGLLCQ VQPAYTSMVA STHLPQLQCR DEGAGKEQHI
ATSSVMHQPF QVTPTSPIGS SYQSIQTSMY NGPTCLPVNP ASSQEFDPVL FQQDAALSSL
VNLGCQPLSP IPFHSSNSDA TGHLLAHSPH SVQTPPHLQS MGYHCSNAGQ TALSSPVADQ
ITGQPSSHLQ PITYCPSHPG SATAASPAAS HPLASSPISG PSSPQLQPMP YQSPSSGTAS
SPSPTTRMHS GQHSTQAQST GQGGLSVPSS LVCHSLCDPA SFPPGGATVS IKPEPEDQEP
NFATIGLQDI TLDDVNEIIG RDMSQISVSQ ATEVMRDTPL PGPASPDLMT SHSAH
