NFATC4

This gene encodes a member of the nuclear factor of activated T cells (NFAT) protein family. The encoded protein is part of a DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor stimulation and an inducible nuclear component. NFAT proteins are activated by the calmodulin-dependent phosphatase, calcineurin. The encoded protein plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of interleukin-2 and interleukin-4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Nuclear Factor Of Activated T Cells 4

Ca2+-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems (PubMed:7749981, PubMed:11514544, PubMed:11997522, PubMed:17875713, PubMed:17213202, PubMed:18668201, PubMed:25663301).

Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4 (PubMed:7749981, PubMed:18668201, PubMed:18347059).

Along with NFATC3, involved in embryonic heart development. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function (By similarity).

Transactivates many genes involved in the cardiovascular system, including AGTR2, NPPB/BNP (in synergy with GATA4), NPPA/ANP/ANF and MYH7/beta-MHC (By similarity).

Involved in the regulation of adult hippocampal neurogenesis. Involved in BDNF-driven pro-survival signaling in hippocampal adult-born neurons. Involved in the formation of long-term spatial memory and long-term potentiation (By similarity).

In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during the developmental critical period, when auditory neurons depend on afferent input for survival (By similarity).

Binds to and activates the BACE1/Beta-secretase 1 promoter, hence may regulate the proteolytic processing of the amyloid precursor protein (APP) (PubMed:25663301).

Plays a role in adipocyte differentiation (PubMed:11997522).

May be involved in myoblast differentiation into myotubes (PubMed:17213202).

Binds the consensus DNA sequence 5'-GGAAAAT-3' (Probable). In the presence of CREBBP, activates TNF transcription (PubMed:11514544).

Binds to PPARG gene promoter and regulates its activity (PubMed:11997522).

Binds to PPARG and REG3G gene promoters (By similarity).

Brain-derived neurotrophic factor receptor signaling pathway Source: UniProtKB
Branching involved in blood vessel morphogenesis Source: Ensembl
Calcineurin-NFAT signaling cascade Source: GO_Central
Cellular respiration Source: Ensembl
Cellular response to lithium ion Source: Ensembl
Cellular response to UV Source: Ensembl
Heart development Source: Ensembl
Inflammatory response Source: ProtInc
Intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
Long-term memory Source: UniProtKB
Long-term synaptic potentiation Source: UniProtKB
Muscle cell development Source: Ensembl
Negative regulation of chromatin binding Source: Ensembl
Negative regulation of dendrite morphogenesis Source: Ensembl
Negative regulation of miRNA transcription Source: BHF-UCL
Negative regulation of neuron apoptotic process Source: UniProtKB
Negative regulation of protein binding Source: Ensembl
Negative regulation of synapse maturation Source: Ensembl
Negative regulation of Wnt signaling pathway Source: Ensembl
Positive regulation of apoptotic signaling pathway Source: Ensembl
Positive regulation of transcription by RNA polymerase II Source: Ensembl
Positive regulation of tumor necrosis factor production Source: Ensembl
Regulation of transcription by RNA polymerase II Source: GO_Central
Smooth muscle cell differentiation Source: Ensembl

Cytosol
Nucleus
Note: When hyperphosphorylated, localizes in the cytosol. When intracellular Ca2+ levels increase, dephosphorylation by calcineurin/PPP3CA leads to translocation into the nucleus (PubMed:11997522, PubMed:18347059). MAPK7/ERK5 and MTOR regulate NFATC4 nuclear export through phosphorylation at Ser-168 and Ser-170 (PubMed:18347059).

Phosphorylated by NFATC-kinases; dephosphorylated by calcineurin/PPP3CA. Phosphorylated on Ser-168 and Ser-170 by MTOR, IRAK1, MAPK7/ERK5 and MAPK14/p38, on Ser-213 and Ser-217 by MAPK8/JNK1 and MAPK9/JNK2, and on Ser-289 and Ser-344 by RPS6KA3 (PubMed:11997522, PubMed:17875713, PubMed:17213202, PubMed:18347059). Phosphorylated by GSK3B (PubMed:18347059). Phosphorylation by GSK3B markedly increases NFATC4 ubiquitination (By similarity). Phosphorylation at Ser-168 and Ser-170 is stimulated by UV irradiation (PubMed:18347059). Phosphorylation determines subcellular location: the hyperphosphorylated protein is cytosolic, while the dephosphorylated form is targeted to the nucleus.
Ubiquitinated, leading to degradation by the proteasome. Ubiquitination may be stimulated by GSK3B-dependent phosphorylation. Polyubiquitin linkage mainly occurs through 'Lys-48'.