nuclear factor of activated T-cells cytoplasmic 4 (NFATc4, NFAT3)
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Function
- role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 & IL-4
- transcriptionally repressed by estrogen receptors; inhibition is further enhanced by estrogen
- increases transcriptional activity of PPARG
- role in adipocyte differentiation
- may play a role in myotube differentiation
- may play a role in cardiac development & hypertrophy
- may play a role in deafferentation-induced apoptosis of sensory neurons
- phosphorylated by NFATC-kinases
- dephosphorylated by calcineurin
- phosphorylated on Ser-168 & Ser-170 by FRAP1, IRAK1, MAPK7 & MAPK14, on Ser-213 & Ser-217 by MAPK8 & MAPK9, & on Ser-289 & Ser-344 by RPS6KA3
- phosphorylated by GSK3B
- ubiquitinated, leading to its degradation by the proteasome
- ubiquitination can be further facilitated via GSK3B-dependent phosphorylation
- polyubiquitin linkage is mainly through Lys-48
- member of the multicomponent NFATC transcription complex
- binds to DNA as monomer
- interacts with CREBBP, GATA4, IRAK1, MAPK8, MAPK9 & RPS6KA3
Structure
- Rel similarity domain (RSD) allows DNA-binding & cooperative interactions with AP1 factors (putative)
- contains 1 IPT/TIG domain
- contains 1 RHD (Rel-like) domain
Compartment
- cytoplasm. nucleus
- cytoplasmic for the phosphorylated form
- 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 & transient Ca+2 signals
- the subcellular localization of NFATC plays a key role in regulation of gene transcription
Alternative splicing
named isoforms=24
Expression
- highly expressed in placenta, lung, kidney, testis & ovary
- weakly expressed in spleen & thymus
- not expressed in peripheral blood lymphocytes
- detected in hippocampus