Nuclear factor of activated T-cells, cytoplasmic 2

Names and origin

Protein names

Recommended name:
    Nuclear factor of activated T-cells, cytoplasmic 2
Alternative name(s):
    T-cell transcription factor NFAT1
    NFAT pre-existing subunit
      Short name=NF-ATp

Gene names

Name:	Nfatc2
Synonyms:	Nfat1, Nfatp

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

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Protein attributes

Sequence length	927 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2, IL-3, IL-4, TNF-alpha or GM-CSF.
Subunit structure	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. The phosphorylated form specifically interacts with XPO1; which mediates nuclear export. NFATC proteins bind to DNA as monomers. Interacts with NFATC2IP. Ref.6 Ref.9
Subcellular location	Cytoplasm. Nucleus. 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. Ref.9
Tissue specificity	Expressed in thymus, spleen, heart, testis, brain, placenta, muscle and pancreas.
Domain	Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors By similarity.
Post-translational modification	In resting cells, phosphorylated by NFATC-kinase on at least 18 sites in the 99-365 region. Upon cell stimulation, all these sites except Ser-245 are dephosphorylated by calcineurin. Dephosphorylation induces a conformational change that simultaneously exposes an NLS and masks an NES, which results in nuclear localization. Simultaneously, one site among Ser-53; Ser-54 and Ser-56 is phosphorylated; which is required for full transcriptional activity. Ref.9 Ref.10
Sequence similarities	Contains 1 RHD (Rel-like) domain.
Sequence caution	The sequence AAC52929.1 differs from that shown. Reason: Miscellaneous discrepancy. Chimeric cDNA fused with Phyhd1 (Lrrc8a).

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Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator
PTM	Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	cytokine production Inferred from direct assay. Source: MGI positive regulation of transcription from RNA polymerase II promoter Ref.3 Inferred from direct assay. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Inferred from direct assay. Source: MGI nucleus Inferred from direct assay. Source: MGI
Molecular function	sequence-specific DNA binding Inferred from direct assay. Source: MGI transcription activator activity Ref.3 Inferred from direct assay. Source: MGI transcription factor activity Inferred from direct assay. Source: MGI
Complete GO annotation...

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Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform C (identifier: Q60591-3) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform B (identifier: Q60591-2) The sequence of this isoform differs from the canonical sequence as follows: 910-927: VNEIIRKEFSGPPSRNQT → ELIDTHLSWIQNIL

Isoform D (identifier: Q60591-4) The sequence of this isoform differs from the canonical sequence as follows: 619-806: DGQQIWEMEA...QGSTLRHTSS → GPAGTCETRP...PGSSLVLLAL

Isoform A (identifier: Q60591-1) The sequence of this isoform is not available.
Note: Ref.2 (AAC52929) sequence is a chimeric cDNA.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 927

927

Nuclear factor of activated T-cells, cytoplasmic 2

PRO_0000205179

Regions

Repeat

186 – 202

17

1

Repeat

215 – 231

17

2

Repeat

274 – 290

17

3; approximate

Domain

394 – 576

183

RHD

DNA binding

423 – 430

8

Region

111 – 116

6

Calcineurin-binding

Region

119 – 201

83

Trans-activation domain A (TAD-A)

Region

163 – 177

15

Required for cytoplasmic retention of the phosphorylated form

Region

186 – 292

107

3 X approximate SP repeats

Motif

253 – 255

3

Nuclear localization signal

Amino acid modifications

Modified residue

53

1

Phosphoserine Probable

Modified residue

54

1

Phosphoserine Probable

Modified residue

56

1

Phosphoserine Probable

Modified residue

99

1

Phosphoserine Ref.9

Modified residue

110

1

Phosphoserine By similarity

Modified residue

136

1

Phosphoserine Ref.9

Modified residue

170

1

Phosphoserine Probable

Modified residue

173

1

Phosphoserine Probable

Modified residue

174

1

Phosphoserine Probable

Modified residue

176

1

Phosphoserine Probable

Modified residue

177

1

Phosphoserine Probable

Modified residue

179

1

Phosphoserine Probable

Modified residue

182

1

Phosphoserine Probable

Modified residue

215

1

Phosphoserine Ref.9

Modified residue

219

1

Phosphoserine Ref.9

Modified residue

223

1

Phosphoserine Ref.9

Modified residue

238

1

Phosphoserine Ref.9

Modified residue

245

1

Phosphoserine Ref.9

Modified residue

270

1

Phosphoserine Ref.9 Ref.10

Modified residue

276

1

Phosphoserine Ref.9

Modified residue

278

1

Phosphoserine Ref.9

Modified residue

282

1

Phosphoserine Ref.9

Modified residue

328

1

Phosphoserine Ref.9

Modified residue

365

1

Phosphoserine Ref.9

Modified residue

601

1

Phosphothreonine By similarity

Modified residue

757

1

Phosphoserine By similarity

Modified residue

761

1

Phosphoserine By similarity

Modified residue

860

1

Phosphoserine By similarity

Natural variations

Alternative sequence

619 – 806

188

DGQQI…RHTSS → GPAGTCETRPLPISLISADR LSPWLSRLQRNPPGSVFRCS VLLPAPGSSLVLLAL in isoform D.

VSP_005597

Alternative sequence

910 – 927

18

VNEII…SRNQT → ELIDTHLSWIQNIL in isoform B.

VSP_005596

Experimental info

Mutagenesis

112

1

R → A: Lowers dephosphorylation. Ref.7

Mutagenesis

114

1

E → A: Lowers dephosphorylation. Ref.7

Mutagenesis

116

1

T → A: No dephosphorylation. Ref.7

Mutagenesis

164

1

R → A: Induces aberrant nuclear localization of the phosphorylated form. Ref.9

Mutagenesis

423

1

R → A: Decrease in binding to DNA. Ref.5

Mutagenesis

425

1

H → A: No change in binding to DNA. Ref.5

Mutagenesis

426

1

Y → A: Decrease in binding to DNA. Ref.5

Mutagenesis

428

1

T → A: No change in binding to DNA. Ref.5

Mutagenesis

428

1

T → C: No change in binding to DNA and confers DNA-binding sensitivity to sulfhydryl modifications. Ref.5

Mutagenesis

429

1

E → A: Decrease in binding to DNA. Ref.5

Sequence conflict

78

1

L → P in AAK49895. Ref.3

Sequence conflict

287

1

L → P in AAC52929. Ref.2

Sequence conflict

287

1

L → P in AAC52930. Ref.2

Sequence conflict

287

1

L → P in AAC52931. Ref.2

Sequence conflict

802

1

R → P in CAM15671. Ref.4

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Sequences

Sequence

Length

Mass (Da)

Tools

Isoform C [UniParc].

Last modified February 5, 2008. Version 2.
Checksum: F21E7BA887DAD40D
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FASTA

927

100,079

        10         20         30         40         50         60 
MDVPEPQPDP DGGDGPGHEP GGSPQDELDF SILFDYDYLN PIEEEPIAHK AISSPSGLAY 

        70         80         90        100        110        120 
PDDVLDYGLK PCNPLASLSG EPPGRFGEPD SIGFQNFLSP VKPAGASGPS PRIEITPSHE 

       130        140        150        160        170        180 
LMQAGGALRG RDAGLSPEQP ALALAGVAAS PRFTLPVPGY EGYREPLCLS PASSGSSASF 

       190        200        210        220        230        240 
ISDTFSPYTS PCVSPNNAGP DDLCPQFQNI PAHYSPRTSP IMSPRTSLAE DSCLGRHSPV 

       250        260        270        280        290        300 
PRPASRSSSP GAKRRHSCAE ALVAPLPAAS PQRSRSPSPQ PSPHVALQDD SIPAGYPPTA 

       310        320        330        340        350        360 
GSAVLMDALN TLATDSPCGI PSKIWKTSPD PTPVSTAPSK AGLARHIYPT VEFLGPCEQE 

       370        380        390        400        410        420 
ERRNSAPESI LLVPPTWPKQ LVPAIPICSI PVTASLPPLE WPLSNQSGSY ELRIEVQPKP 

       430        440        450        460        470        480 
HHRAHYETEG SRGAVKAPTG GHPVVQLHGY MENKPLGLQI FIGTADERIL KPHAFYQVHR 

       490        500        510        520        530        540 
ITGKTVTTTS YEKIVGNTKV LEIPLEPKNN MRATIDCAGI LKLRNADIEL RKGETDIGRK 

       550        560        570        580        590        600 
NTRVRLVFRV HVPEPSGRIV SLQAASNPIE CSQRSAHELP MVERQDMDSC LVYGGQQMIL 

       610        620        630        640        650        660 
TGQNFTAESK VVFMEKTTDG QQIWEMEATV DKDKSQPNML FVEIPEYRNK HIRVPVKVNF 

       670        680        690        700        710        720 
YVINGKRKRS QPQHFTYHPV PAIKTEPSDE YEPSLICSPA HGGLGSQPYY PQHPMLAESP 

       730        740        750        760        770        780 
SCLVATMAPC QQFRSGLSSP DARYQQQSPA AALYQRSKSL SPGLLGYQQP SLLAAPLGLA 

       790        800        810        820        830        840 
DAHRSVLVHA GSQGQGQGST LRHTSSASQQ ASPVIHYSPT NQQLRGGGHQ EFQHIMYCEN 

       850        860        870        880        890        900 
FGPSSARPGP PPINQGQRLS PGAYPTVIQQ QTAPSQRAAK NGPSDQKEAL PTGVTVKQEQ 

       910        920 
NLDQTYLDDV NEIIRKEFSG PPSRNQT

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Isoform B.

Checksum: A2B5D0456A75A83F
Show »

FASTA

923

99,701

        10         20         30         40         50         60 
MDVPEPQPDP DGGDGPGHEP GGSPQDELDF SILFDYDYLN PIEEEPIAHK AISSPSGLAY 

        70         80         90        100        110        120 
PDDVLDYGLK PCNPLASLSG EPPGRFGEPD SIGFQNFLSP VKPAGASGPS PRIEITPSHE 

       130        140        150        160        170        180 
LMQAGGALRG RDAGLSPEQP ALALAGVAAS PRFTLPVPGY EGYREPLCLS PASSGSSASF 

       190        200        210        220        230        240 
ISDTFSPYTS PCVSPNNAGP DDLCPQFQNI PAHYSPRTSP IMSPRTSLAE DSCLGRHSPV 

       250        260        270        280        290        300 
PRPASRSSSP GAKRRHSCAE ALVAPLPAAS PQRSRSPSPQ PSPHVALQDD SIPAGYPPTA 

       310        320        330        340        350        360 
GSAVLMDALN TLATDSPCGI PSKIWKTSPD PTPVSTAPSK AGLARHIYPT VEFLGPCEQE 

       370        380        390        400        410        420 
ERRNSAPESI LLVPPTWPKQ LVPAIPICSI PVTASLPPLE WPLSNQSGSY ELRIEVQPKP 

       430        440        450        460        470        480 
HHRAHYETEG SRGAVKAPTG GHPVVQLHGY MENKPLGLQI FIGTADERIL KPHAFYQVHR 

       490        500        510        520        530        540 
ITGKTVTTTS YEKIVGNTKV LEIPLEPKNN MRATIDCAGI LKLRNADIEL RKGETDIGRK 

       550        560        570        580        590        600 
NTRVRLVFRV HVPEPSGRIV SLQAASNPIE CSQRSAHELP MVERQDMDSC LVYGGQQMIL 

       610        620        630        640        650        660 
TGQNFTAESK VVFMEKTTDG QQIWEMEATV DKDKSQPNML FVEIPEYRNK HIRVPVKVNF 

       670        680        690        700        710        720 
YVINGKRKRS QPQHFTYHPV PAIKTEPSDE YEPSLICSPA HGGLGSQPYY PQHPMLAESP 

       730        740        750        760        770        780 
SCLVATMAPC QQFRSGLSSP DARYQQQSPA AALYQRSKSL SPGLLGYQQP SLLAAPLGLA 

       790        800        810        820        830        840 
DAHRSVLVHA GSQGQGQGST LRHTSSASQQ ASPVIHYSPT NQQLRGGGHQ EFQHIMYCEN 

       850        860        870        880        890        900 
FGPSSARPGP PPINQGQRLS PGAYPTVIQQ QTAPSQRAAK NGPSDQKEAL PTGVTVKQEQ 

       910        920 
NLDQTYLDDE LIDTHLSWIQ NIL

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Isoform D.

Checksum: 1A8246FF98E219B8
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FASTA

794

85,181

Isoform A (Sequence not available).

FASTA

–

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of the cyclosporin-sensitive T cell transcription factor NFATp." McCaffrey P.G., Luo C., Kerpolla T.K., Jain J., Badalian T.M., Ho A.M., Burgeon E., Lane W.S., Lambert J.N., Curran T., Verdine G.L., Rao A., Hogan P.G. Science 262:750-754(1993) [PubMed: 8235597] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE (ISOFORM A).
[2]	"Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes." Luo C., Burgeon E., Carew J.A., McCaffrey P.G., Badalian T.M., Lane W.S., Hogan P.G., Rao A. Mol. Cell. Biol. 16:3955-3966(1996) [PubMed: 8668213] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; B AND C).
[3]	"Identification and characterization of a novel nuclear factor of activated T-cells-1 isoform expressed in mouse brain." Plyte S., Boncristiano M., Fattori E., Galvagni F., Paccani S.R., Majolini M.B., Oliviero S., Ciliberto G., Telford J.L., Baldari C.T. J. Biol. Chem. 276:14350-14358(2001) [PubMed: 11278367] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM D). Strain: C57BL/6. Tissue: Brain.
[4]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[5]	"A similar DNA-binding motif in NFAT family proteins and the Rel homology region." Jain J., Burgeon E., Badalian T.M., Hogan P.G., Rao A. J. Biol. Chem. 270:4138-4145(1995) [PubMed: 7876165] [Abstract] Cited for: MUTAGENESIS OF ARG-423; HIS-425; TYR-426; THR-428 AND GLU-429.
[6]	"NF-AT-driven interleukin-4 transcription potentiated by NIP45." Hodge M.R., Chun H.J., Rengarajan J., Alt A., Lieberson R., Glimcher L.H. Science 274:1903-1905(1996) [PubMed: 8943202] [Abstract] Cited for: INTERACTION WITH NFATC2IP.
[7]	"Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT." Aramburu J., Garcia-Cozar F., Raghavan A., Okamura H., Rao A., Hogan P.G. Mol. Cell 1:627-637(1998) [PubMed: 9660947] [Abstract] Cited for: MUTAGENESIS OF ARG-112; GLU-114 AND THR-116.
[8]	"Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT." Crabtree G.R. Cell 96:611-614(1999) [PubMed: 10089876] [Abstract] Cited for: REVIEW.
[9]	"Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity." Okamura H., Aramburu J., Garcia-Rodriguez C., Viola J.P.B., Raghavan A., Tahiliani M., Zhang X., Qin J., Hogan P.G., Rao A. Mol. Cell 6:539-550(2000) [PubMed: 11030334] [Abstract] Cited for: PHOSPHORYLATION AT SER-99; SER-136; SER-170; SER-173; SER-174; SER-176; SER-177; SER-179; SER-182; SER-215; SER-219; SER-223; SER-238; SER-245; SER-270; SER-276; SER-278; SER-282; SER-328 AND SER-365, SUBCELLULAR LOCATION, INTERACTION WITH XPO1, MUTAGENESIS OF ARG-164, MASS SPECTROMETRY.
[10]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed: 18973353] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-270, MASS SPECTROMETRY.
+	Additional computationally mapped references.

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Cross-references

Sequence databases
EMBL GenBank DDBJ	U02079 mRNA. Translation: AAC52929.1. Sequence problems. U36575 mRNA. Translation: AAC52930.1. U36576 mRNA. Translation: AAC52931.1. AF289078 mRNA. Translation: AAK49895.1. AL840639, AL844575 Genomic DNA. Translation: CAM15662.1. AL840639, AL844575 Genomic DNA. Translation: CAM15663.1. AL844575 Genomic DNA. Translation: CAM15669.1. AL844575, AL840639 Genomic DNA. Translation: CAM15670.1. AL844575, AL840639 Genomic DNA. Translation: CAM15671.1.
IPI	IPI00229456. IPI00314662. IPI00911162.
PIR	A48753.
RefSeq	NP_001032254.1. NP_001129545.1. NP_035029.2.
UniGene	Mm.116802
3D structure databases
SMR	Q60591. Positions 394-680.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q60591. 8 interactions.
STRING	Q60591.
PTM databases
PhosphoSite	Q60591.
Proteomic databases
PRIDE	Q60591.
Genome annotation databases
Ensembl	ENSMUST00000029057; ENSMUSP00000029057; ENSMUSG00000027544; Mus musculus. [Genome view] ENSMUST00000074618; ENSMUSP00000074198; ENSMUSG00000027544; Mus musculus. [Genome view] ENSMUST00000099068; ENSMUSP00000096667; ENSMUSG00000027544; Mus musculus. [Genome view] ENSMUST00000109186; ENSMUSP00000104813; ENSMUSG00000027544; Mus musculus. [Genome view]
GeneID	18019.
KEGG	mmu:18019.
UCSC	uc008oau.1. mouse. uc008oav.1. mouse.
Organism-specific databases
CTD	18019.
MGI	MGI:102463. Nfatc2.
Phylogenomic databases
eggNOG	roNOG07381.
HOVERGEN	Q60591.
InParanoid	Q60591.
Gene expression databases
ArrayExpress	Q60591.
Bgee	Q60591.
Genevestigator	Q60591.
GermOnline	ENSMUSG00000027544. Mus musculus.
Family and domain databases
InterPro	IPR013783. Ig-like_fold. IPR014756. Ig_E-set. IPR002909. IPT_TIG_rcpt. IPR008366. NFAT. IPR018286. NFAT_sbgrp. IPR008967. p53-like_TF_DNA-bd. IPR011539. RHD. [Graphical view]
Gene3D	G3DSA:2.60.40.10. Ig-like_fold. 1 hit. G3DSA:2.60.40.340. RHD. 1 hit.
PANTHER	PTHR12533. NFAT. 1 hit.
Pfam	PF00554. RHD. 1 hit. PF01833. TIG. 1 hit. [Graphical view]
PRINTS	PR01789. NUCFACTORATC.
SMART	SM00429. IPT. 1 hit. [Graphical view]
PROSITE	PS01204. REL_1. False negative. PS50254. REL_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	293063.
SOURCE	Search...

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Entry information

Entry name

NFAC2_MOUSE

Accession

Primary (citable) accession number: Q60591
Secondary accession number(s): A2APK2

Q91Y65

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	February 5, 2008
Last modified:	February 9, 2010
This is version 101 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents