NFATc1/αA: The other Face of NFAT Factors in Lymphocytes

The five members of the family of NFAT transcription factors are characterized by an evolutionary conserved DNA binding domain of approximately 300 amino acid (aa) residues. This domain forms a three dimensional structure similar to the DNA binding domain of Rel/NF-κB factors and, therefore, was designated as Rel Similarity Domain (RSD) or Rel Homology Domain (RHD) [1-3]. While the most distantly related NFAT5 shares 41-45% sequence similarity in its RSD with those of genuine NFATc factors NFATc1, c2, c3 and c4, the latter exhibit 68-75% sequence homology between their RSDs [4]. The DNA core motif for the DNA binding of NFAT factors, A/T GGAAA, resembles one half-site of κB motif of NF-κB factors, and there is a subset of κB binding motifs to which NFAT factors can also bind [5,6]. This was shown at the molecular level for the binding of NFATc2 homo-dimers to the κB motifs within the HIV LTR and the Il8 promoter which share the core motif of NFAT binding sites [7,8]. Since NFAT and NF-κB proteins contact identical nucleotides, it is unlikely that both factors can bind at the same time to the same motif. Instead, they appear to compete for DNA binding. This seems to depend on the cellular concentration of both types of factors and other parameters, such as the level of co-factors, as AP-1, which affects the binding of NFATs to DNA.Due to the control by the Ca++/calmodulin-dependent Ser/Thr-protein phosphatase calcineurin (CN; also known as PP2B) [1-3], the four genuine NFATc proteins constitute an own family of transcription factors with individual properties. Although they were described first for human Jurkat leukemic T cells [9] and murine EL-4 thymoma cells [10], they are not only expressed in lymphocytes but also in numerous other cells of the hematopoietic system, and also in cardiomyocytes, muscle, bone and brain cells. While in numerous studies the function of NFAT factors has been investigated in these tissues, in greatest detail the expression and function