The NFAT Family: Structure, Regulation, and Biological Functions

This chapter sheds light on the structure, regulation, and biological functions of the NFAT family, which is a family of transcription factors. The primordial NFAT family member NFAT5/TonEBP is expressed ubiquitously in mammalian cells and regulates the response to hypertonic stress. NFAT5 is also likely to be involved in regulating diverse other biological programs. The DNA binding domains of all NFAT and NFкB/Rel family members have two domains, an N-terminal specificity domain involved in making base specific DNA contacts, and a C-terminal domain involved in dimer formation. Together these domains constitute the Rel homology region (RHR) common to all members of the extended NFAT/NFкB/Rel family. NFAT proteins can also function as dimeric transcription factors at quasi-palindromic sites that resemble NFкB binding sites. The calcium regulated NFAT proteins are activated by ligand binding to a variety of cell surface receptors. The common feature of the receptors is their ability to activate phosphatidylinositol specific phospholipase C (PLC), thereby inducing calcium influx across the plasma membrane. NFAT dependent gene transcription is exquisitely sensitive to changes in intracellular calcium concentration. Even in the continuous presence of stimulus, levels may oscillate depending on specific parameters of receptor occupancy and desensitization. Interaction with calcineurin is central to the calcium responsiveness of NFAT1-4. The major calcineurin docking site on NFAT is located at the N-terminus of the regulatory domain and has the consensus sequence PxIxIT. Substitution of the PxIxIT sequence of NFAT1 with a higher affinity version obtained by peptide selection increases the basal sensitivity of NFAT.