Reviewed, UniProtKB/Swiss-Prot Q8K120 (NFAC4_MOUSE)

Names and origin

Protein names

Recommended name:
    Nuclear factor of activated T-cells, cytoplasmic 4
      Short name=NF-ATc4
      Short name=NFATc4
Alternative name(s):
    T-cell transcription factor NFAT3
      Short name=NF-AT3

Gene names

Name:	Nfatc4
Synonyms:	Nfat3

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

Protein attributes

Sequence length	901 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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 and IL-4. Transcriptionally repressed by estrogen receptors; this inhibition is further enhanced by estrogen. Increases the transcriptional activity of PPARG and has a direct role in adipocyte differentiation. May play an important role in myotube differentiation By similarity. May play a critical role in cardiac development and hypertrophy. May play a role in deafferentation-induced apoptosis of sensory neurons. Ref.6 Ref.7 Ref.8 UniProtKB Q14934
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. NFATC proteins bind to DNA as monomers. Interacts with CREBBP, GATA4, IRAK1, MAPK8, MAPK9 and RPS6KA3. Ref.6 UniProtKB Q14934
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.
Tissue specificity	Expressed in all tissues analyzed including brain, lung, heart, testis and muscle. Ref.2
Domain	Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors By similarity. UniProtKB O95644
Post-translational modification	Phosphorylated by NFATC-kinases; dephosphorylated by calcineurin. Phosphorylated on Ser-168 and Ser-170 by FRAP1, IRAK1, MAPK7 and MAPK14, on Ser-213 and Ser-217 by MAPK8 and MAPK9, and on Ser-289 and Ser-344 by RPS6KA3. Phosphorylated by GSK3B. Ref.9 UniProtKB Q14934 Ubiquitinated, leading to its degradation by the proteasome and reduced transcriptional activity. Ubiquitination and reduction in transcriptional activity can be further facilitated through GSK3B-dependent phosphorylation. Polyubiquitin linkage is mainly through 'Lys-48' By similarity. UniProtKB Q14934
Sequence similarities	Contains 1 IPT/TIG domain. Contains 1 RHD (Rel-like) domain.

Ontologies

Keywords
Biological process	Differentiation Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator
PTM	Phosphoprotein Ubl conjugation
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW cellular respiration Inferred from direct assay. Source: MGI heart development Inferred from genetic interaction. Source: MGI regulation of transcription, DNA-dependent Inferred from direct assay. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	transcription factor activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 Ref.2 Ref.5 Ref.1 Ref.3 Ref.4 (identifier: Q8K120-1)

Also known as: I-IXL;

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 2 Ref.2 (identifier: Q8K120-2)

Also known as: I-IXi;

The sequence of this isoform differs from the canonical sequence as follows:
     880-894: VSEIIGRDLSGFPAR → GGCGTGGCECK
     895-901: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 901	901	Nuclear factor of activated T-cells, cytoplasmic 4		PRO_0000367433
Regions
	Repeat	213 – 229	17	SP 1
	Repeat	277 – 293	17	SP 2; approximate
	Domain	401 – 582	182	RHD
	Domain	586 – 683	98	IPT/TIG
	DNA binding	430 – 437	8	By similarity UniProtKB Q14934
	Region	114 – 119	6	Calcineurin-binding By similarity UniProtKB Q14934
	Region	213 – 293	81	2 approximate SP repeats
	Motif	268 – 270	3	Nuclear localization signal
	Motif	672 – 674	3	Nuclear localization signal
	Compositional bias	23 – 327	305	Pro-rich
	Compositional bias	692 – 836	145	Pro-rich
Amino acid modifications
	Modified residue	168	1	Phosphoserine; by MAPK7 and MAPK14 Ref.9
	Modified residue	170	1	Phosphoserine; by MAPK7 and MAPK14 Ref.9
	Modified residue	213	1	Phosphoserine; by MAPK8 and MAPK9 By similarity UniProtKB Q14934
	Modified residue	217	1	Phosphoserine; by MAPK8 and MAPK9 By similarity UniProtKB Q14934
	Modified residue	272	1	Phosphoserine By similarity UniProtKB Q14934
	Modified residue	289	1	Phosphoserine; by RPS6KA3 By similarity UniProtKB Q14934
	Modified residue	334	1	Phosphoserine; by RPS6KA3 By similarity UniProtKB Q14934
Natural variations
	Alternative sequence	880 – 894	15	VSEII…GFPAR → GGCGTGGCECK in isoform 2. Ref.2		VSP_053054
	Alternative sequence	895 – 901	7	Missing in isoform 2. Ref.2		VSP_053055
Experimental info
	Sequence conflict	135	1	S → P in AAH28928. Ref.5
	Sequence conflict	379 – 380	2	AV → TM in AAG39446. Ref.1
	Sequence conflict	379 – 380	2	AV → TM in AAF98174. Ref.1
	Sequence conflict	394 – 395	2	HS → QT in AAG39446. Ref.1
	Sequence conflict	394 – 395	2	HS → QT in AAF98174. Ref.1
	Sequence conflict	562	1	G → S in AAH28928. Ref.5
	Sequence conflict	589 – 590	2	ET → GD in AAG39446. Ref.1
	Sequence conflict	589 – 590	2	ET → GD in AAF98174. Ref.1
	Sequence conflict	662	1	V → I in AAG39446. Ref.1
	Sequence conflict	662	1	V → I in AAF98174. Ref.1
	Sequence conflict	730	1	P → L in AAG39446. Ref.1
	Sequence conflict	730	1	P → L in AAF98174. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (I-IXL) [UniParc]. Last modified March 24, 2009. Version 2. Checksum: 5977695F888F6538	FASTA	901	95,782
	10 20 30 40 50 60 MGAASCEDEE LEFKLVFGEE KEPPPLGPGG PGEELDSEDT PPCCRLALGE PLPYGAAPIG 70 80 90 100 110 120 IPRPPPPRPG MHSPPPRPAP SPGTWESQPA RSVRLGGPGG NAGGAGGGRV LECPSIRITS 130 140 150 160 170 180 ISPTPDPPTS LEDTSETWGD GSPRDYPPPE GFGGYREAGG QGGGAFFSPS PGSSSLSSWS 190 200 210 220 230 240 FFSDASDEAA LYAACDEVES ELNEAASRFG LSSPLPSPRA SPRPWTPEDP WSLYGPSSGG 250 260 270 280 290 300 RAPEDSWLLL SAPGPVPASP RPASPCGKRR YSSSGTPSSA SPALSRRGSL GEEGPEPPPP 310 320 330 340 350 360 PPLPLVRDPS SPGPFDYVGA PPTESIPQKT RRTSSEQAVA LPRSEEPPSC NGKLPSGTED 370 380 390 400 410 420 SVAAPGALRK EVAGMDYLAV PSPLAWSKAR IGGHSPIFRT SALPPLDWPL PSQYEQLELR 430 440 450 460 470 480 IEVQPRAHHR AHYETEGSRG AVKAAPGGHP VVKLLGYSEK PLTLQMFIGT ADERSLRPHA 490 500 510 520 530 540 FYQVHRITGK MVATASYEAV VSGTKVLEMT LLPENNMAAN IDCAGILKLR NSDIELRKGE 550 560 570 580 590 600 TDIGRKNTRV RLVFRVHVPQ GGGKVVSVQA ASVPIECSQR SAQELPQVET YSPSACSVRG 610 620 630 640 650 660 GEELVLTGSN FLPDSKVVFI ERGPDGKLQW EEEAAVNRLQ SSEVTLTLTI PEYSNKRVSR 670 680 690 700 710 720 PVQVYFYVSN GRRKRSPTQS FKFLPVVFKE EPLPDSSLRG FPSTSGPPFG PDVDFSPPRP 730 740 750 760 770 780 PYPSYPHEDP AYETPYLSEG FGYSTPALYP QTGPPPSYRS GLRMFPETGG TTGCARLPSV 790 800 810 820 830 840 SFLPRPFPGD QYGGQGSSFA LGLPFSPPAP FRPPLPSSPP LEDPFHPQSA IHPLPPEGYN 850 860 870 880 890 900 EVGPGYTPGE GASEQEKARG GYSSGFRDSV PIQGITLEEV SEIIGRDLSG FPARPGEEPP A
	Isoform 2 (I-IXi). Checksum: 1083BBF9972F0742	FASTA	890	94,459
	10 20 30 40 50 60 MGAASCEDEE LEFKLVFGEE KEPPPLGPGG PGEELDSEDT PPCCRLALGE PLPYGAAPIG 70 80 90 100 110 120 IPRPPPPRPG MHSPPPRPAP SPGTWESQPA RSVRLGGPGG NAGGAGGGRV LECPSIRITS 130 140 150 160 170 180 ISPTPDPPTS LEDTSETWGD GSPRDYPPPE GFGGYREAGG QGGGAFFSPS PGSSSLSSWS 190 200 210 220 230 240 FFSDASDEAA LYAACDEVES ELNEAASRFG LSSPLPSPRA SPRPWTPEDP WSLYGPSSGG 250 260 270 280 290 300 RAPEDSWLLL SAPGPVPASP RPASPCGKRR YSSSGTPSSA SPALSRRGSL GEEGPEPPPP 310 320 330 340 350 360 PPLPLVRDPS SPGPFDYVGA PPTESIPQKT RRTSSEQAVA LPRSEEPPSC NGKLPSGTED 370 380 390 400 410 420 SVAAPGALRK EVAGMDYLAV PSPLAWSKAR IGGHSPIFRT SALPPLDWPL PSQYEQLELR 430 440 450 460 470 480 IEVQPRAHHR AHYETEGSRG AVKAAPGGHP VVKLLGYSEK PLTLQMFIGT ADERSLRPHA 490 500 510 520 530 540 FYQVHRITGK MVATASYEAV VSGTKVLEMT LLPENNMAAN IDCAGILKLR NSDIELRKGE 550 560 570 580 590 600 TDIGRKNTRV RLVFRVHVPQ GGGKVVSVQA ASVPIECSQR SAQELPQVET YSPSACSVRG 610 620 630 640 650 660 GEELVLTGSN FLPDSKVVFI ERGPDGKLQW EEEAAVNRLQ SSEVTLTLTI PEYSNKRVSR 670 680 690 700 710 720 PVQVYFYVSN GRRKRSPTQS FKFLPVVFKE EPLPDSSLRG FPSTSGPPFG PDVDFSPPRP 730 740 750 760 770 780 PYPSYPHEDP AYETPYLSEG FGYSTPALYP QTGPPPSYRS GLRMFPETGG TTGCARLPSV 790 800 810 820 830 840 SFLPRPFPGD QYGGQGSSFA LGLPFSPPAP FRPPLPSSPP LEDPFHPQSA IHPLPPEGYN 850 860 870 880 890 EVGPGYTPGE GASEQEKARG GYSSGFRDSV PIQGITLEEG GCGTGGCECK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Evolutionary relationships among Rel domains indicate functional diversification by recombination." Graef I.A., Gastier J.M., Francke U., Crabtree G.R. Proc. Natl. Acad. Sci. U.S.A. 98:5740-5745(2001) [PubMed: 11344309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1). Strain: 129/SvEv.
[2]	"Alternative splicing and expression of human and mouse NFAT genes." Vihma H., Pruunsild P., Timmusk T. Genomics 92:279-291(2008) [PubMed: 18675896] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY. Strain: C57BL/6.
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Rathke gland.
[4]	Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Mammary tumor.
[6]	"A calcineurin-dependent transcriptional pathway for cardiac hypertrophy." Molkentin J.D., Lu J.-R., Antos C.L., Markham B., Richardson J., Robbins J., Grant S.R., Olson E.N. Cell 93:215-228(1998) [PubMed: 9568714] [Abstract] Cited for: FUNCTION, INTERACTION WITH GATA4.
[7]	"Dosage-dependent transcriptional regulation by the calcineurin/NFAT signaling in developing myocardium transition." Yang X.Y., Yang T.T.C., Schubert W., Factor S.M., Chow C.-W. Dev. Biol. 303:825-837(2007) [PubMed: 17198697] [Abstract] Cited for: FUNCTION.
[8]	"Deafferentation-induced activation of NFAT (nuclear factor of activated T-cells) in cochlear nucleus neurons during a developmental critical period: a role for NFATc4-dependent apoptosis in the CNS." Luoma J.I., Zirpel L. J. Neurosci. 28:3159-3169(2008) [PubMed: 18354019] [Abstract] Cited for: FUNCTION.
[9]	"The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT." Wang D., Fasciano S., Li L. Mol. Immunol. 45:3902-3908(2008) [PubMed: 18691762] [Abstract] Cited for: PHOSPHORYLATION AT SER-168 AND SER-170.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF283284 mRNA. Translation: AAF98174.1. AF309389, AF309388 Genomic DNA. Translation: AAG39446.1. EU887656 mRNA. Translation: ACG55676.1. EU887657 mRNA. Translation: ACG55677.1. AK159078 mRNA. Translation: BAE34797.1. CH466535 Genomic DNA. Translation: EDL36234.1. BC028928 mRNA. Translation: AAH28928.1.
IPI	IPI00409935. IPI00923633.
RefSeq	NP_001161818.1. NP_076188.3.
UniGene	Mm.27908
3D structure databases
HSSP	HSSP built from PDB template 1A66 based on UniProtKB O95644.
SMR	Q8K120. Positions 401-686.
ModBase	Search...
Protein-protein interaction databases
STRING	Q8K120.
Proteomic databases
PRIDE	Q8K120.
Genome annotation databases
Ensembl	ENSMUST00000024179; ENSMUSP00000024179; ENSMUSG00000023411; Mus musculus. [Genome view]
GeneID	73181.
KEGG	mmu:73181.
Organism-specific databases
CTD	73181.
MGI	MGI:1920431. Nfatc4.
Phylogenomic databases
eggNOG	roNOG04442.
HOGENOM	HBG717170.
HOVERGEN	Q8K120.
InParanoid	Q8K120.
OMA	FSPPAPF.
OrthoDB	EOG9Z390M.
PhylomeDB	Q8K120.
Gene expression databases
ArrayExpress	Q8K120.
Bgee	Q8K120.
Genevestigator	Q8K120.
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	337621.
SOURCE	Search...

Entry information

Entry name

NFAC4_MOUSE

Accession

Primary (citable) accession number: Q8K120
Secondary accession number(s): B5B2X2, Q3TXW7, Q9EP91

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 24, 2009
Last sequence update:	March 24, 2009
Last modified:	February 9, 2010
This is version 58 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)