Nuclear factor of activated T-cells (NFAT)
• Major transcription factor found in B-cells, T-cells, NK cells, mast cells, and monocytes as well as in some nonhematopoietic cells
• Possess both a nuclear localization signal (NLS) encoded in its amino acids and a nuclear export signal (NES).
• In resting cells the NLS is phosphorylated and thus inactive. The NES is recognized and phosphorylated/activated by glycogen synthase kinase 3 (GSK3) which quickly exports NFAT if it finds its way into the nucleus. Both ensure that resting NFAT remains in the cytosol.
• Antigenic stimulation of the cell results in increased levels of calcium by action of IP3 on the ER, which in turn activates calmodulin. The calmodulin – calcium complex activates calcineurin which dephosphorylates NFAT, allowing it to enter the nucleus. Downregulation of GSK3 by other signals allows NFAT to associate with AP-1 (formed from Fos and Jun from MAP kinase pathway) and regulate transcription of genes such as the gene for Il-2.
• Cyclosporin A and FK506 inhibit calcineurin and thus the activation of T-cells. Thus they are powerful immunosuppressive drugs useful in preventing graft rejection.