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FLASH GENE

Symbol

NFATC4

contributors: mct/npt - updated : 15-05-2017

HGNC name	nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4
HGNC id	7778

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	14q12      Physical location : 24.836.144 - 24.848.808
Synonym name	T cell transcription factor NFAT3
	cytoplasmic nuclear factor of activated T-cells 4
Synonym symbol(s)	NFAT3, NF-ATc4, NF-AT3

DNA

TYPE	functioning gene
STRUCTURE	12.69 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001136022 10 - 5672 NP_001129494 101.4 964 - 2008 18675896 variant IA-IXL NM_004554 10 splicing 4976 NP_004545 95.3 902 - 2008 18675896 variant ID-IXL using an in-frame downstream AUG, translation termination at a downstream stop codon variant IA-IXS 10 splicing - - 857 - 2008 18675896 variant IA-IXi 9 splicing - - 964 - 2008 18675896 variant IB-IXL 10 splicing - - 915 - 2008 18675896 variant IB-IXS 10 splicing - - 807 - 2008 18675896 variant IB-IXi 9 splicing - - 914 - 2008 18675896 variant IC-IXL 10 splicing - - 934 - 2008 18675896 variant IC-IXS 10 splicing - - 826 - 2008 18675896 variant IC-IXi 9 splicing - - 933 - 2008 18675896 variant ID-IXi 9 splicing - - 901 - 2008 18675896 variant IE-IXL 10 splicing - - 890 - 2008 18675896 variant IE-IXS 10 splicing - - 782 - 2008 18675896 variant IEi-IXS 9 splicing - - 724 - 2008 18675896 variant IEi-IXi 8 splicing - - 831 - 2008 18675896 variant IV-IXL 7 splicing - - 437 - 2008 18675896 variant IV-IXS 7 splicing - - 329 - 2008 18675896 variant IV-IXi 6 splicing - - 436 - 2008 18675896 variant VI-IXL 5 splicing - - 190 - 2008 18675896 variant VI-IXS 5 splicing - - 82 - 2008 18675896 variant VI-IXi 4 splicing - - 189 - 2008 18675896 NM_001320043 11 - 4988 NP_001306972 - 965 - 2008 18675896 NM_001198967 11 - 4664 NP_001185896 - 857 - 2008 18675896 NM_001198965 10 - 4652 NP_001185894 - 794 - 2008 18675896 variant ID-IXS NM_001198966 10 - 4630 NP_001185895 - 832 - 2008 18675896 variant IEi-IXL NM_001288802 9 - 5538 NP_001275731 - 889 - 2008 18675896 variant IE-IXi

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Reproductive female system ovary         female system uterus         male system testis       Urinary kidney         Visual eye anterior segment iris

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cell lineage
cell lines	specifically expressed in ERA positive breast cancer cells
fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	neural tube, somites, placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a RHD (Rel-like) domain
	a Ca2+ sensor/translocation domain

conjugated

PhosphoP

HOMOLOGY

interspecies	homolog to rattus Nfatc4 (92.9 pc)
	homolog to murine Nfatc4 (92.7 pc)

Homologene

FAMILY

activated T-cell (NFAT) family of transcription factors

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
text	cytoplasmic phosphorylated form
	nuclear after activation controlled by calcineurin-mediated dephosphorylation
	nuclear in skeletal muscle, but a predominantly cytosolic localization in other tissues
	remains phosphorylated and localized to the cytosol, only exhibiting nuclear localization following prolonged (1-3 h) depolarization

basic FUNCTION	regulate cytokine gene expression in T cells (to suppress local aberrant growth of vessels)
	required for cardiac development and mitochondrial function
	involved in adipocyte differentiation
	playing a role in learning and memory
	mediating myotube differentiation after activation by RPS6KA3
	implicated as a critical regulator of the cardiac development and hypertrophy
	having an unexpected role as a direct transcriptional repressor of GAP43 expression and may be a more general role in the control of the neuronal outgrowth program
	negative and not a positive regulator of GAP43 during neuronal outgrowth and maturation
	occupies the GAP43 promoter and neurotrophin stimulation reduces promoter occupancy
	may be having the potential to regulate the expression of other genes involved in neuronal outgrowth and maturation
	may plays a role in axonal regeneration after axotomy by controlling the gene expression of neuronal outgrowth genes
	transcriptionally active in fast muscles, i.e., in response to less frequent calcium transients and, presumably, lower Calcineurin activity
	inhibits breast cancer cell motility by targeting the LCN2 gene
	opposing transcriptional activities of FOXP1 and NFATC4 maintaining cardiomyocyte homeostasis
	NFATC4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling (pMID: 22586092)
	is essential in the regulation of adult hippocampal neurogenesis and is a central player of BDNF–driven prosurvival signaling in hippocampal adult-born neurons
	may play a role in promoting the brain secondary damage following intracerebral hemorrhage (ICH)
	NFATC4 might exert its pro-apoptotic function in neuronal apoptosis through extrinsic pathway
	is a key activity-dependent transcriptional regulator of GABA signaling in hippocampal progenitor cells

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

	signaling axis between BDNF and NFATC4 in adult hippocampal neural progenitor cells
	integration of MAPK7 with NFATC4 nucleo-cytoplasmic shuttling and PKA activation in adipocyte signaling
	calcineurin-NFATC4 signaling axis acts as a major regulator of Neural stem cells (NSCs)self-renewal and proliferation by promoting the expression of transcription factors (TFs), including ID2, that contribute to the maintenance of the NSC state

a component

INTERACTION

DNA	binding as a monomer

RNA

small molecule

protein	interacting with ESR1 and ESR2
	functional interaction between lipin 1 (LPIN1) and the nuclear factor of activated T cells c4 (NFATC4) (represses NFATC4 transcriptional activity through protein-protein interaction, and LPIN1 is present at the promoters of NFATC4 transcriptional targets)
	GPC6 is a novel NFATC1, NFATC2, NFATC3, NFATC4 target gene in breast cancer cells that promotes invasive migration through WNT5A signalling
	critical role of CITED2 in cardiomyocyte differentiation by affecting the expression of NFATC4 leading to down-regulation of NKX2.5 and beta-MHC cardiomyocyte genes
	following cyclic stretch, NFATC4 was activated in cardiac fibroblasts in a SDC4- and calcineurin-dependent manner
	TRIM17 also inhibited NFATC4 nuclear translocation and activity
	direct binding of NFATC4 to specific DNA sequences within BACE1 promoter region

cell & other

REGULATION

activated by	neurotrophins and netrins for nuclear localization and stimulation of NFAT-gene transcription and outgrowth of embryonic axons
	calcineurin

repressed by	ESR1 and ESR2 (ESR may play a critical role in regulation of NFAT3 transcriptional activity)

Other	phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217)
	phosphorylated by RPS6KA3
	regulated by the ubiquitin
		proteasome system that plays an important role in regulating NFATC4 stability and transactivation
	regulated by the calcium/calmodulin-dependent phosphatase calcineurin

ASSOCIATED DISORDERS

corresponding disease(s)

Susceptibility

Variant & Polymorphism other	G160A increases the risk of cardiac hypertrophy

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS