The role of NF-AT transcription factors in T cell activation and differentiation11We dedicate this review to Prof. Dr. Rigomar Rieger (Gatersleben), a great scientist and man, on the occasion of his 70th birthday. One of us (E.S.) had the pleasure of working in his department.

Abstract

The family of genuine NF-AT transcription factors consists of four members (NF-AT1 [or NF-ATp], NF-AT2 [or NF-ATc], NF-AT3 and NF-AT4 [or NF-ATx]) which are characterized by a highly conserved DNA binding domain (is designated as Rel similarity domain) and a calcineurin binding domain. The binding of the Ca(2+)-dependent phosphatase calcineurin to this region controls the nuclear import and exit of NF-ATs. This review deals (1) with the structure of NF-AT proteins, (2) the DNA binding of NF-AT factors and their interaction with AP-1, (3) NF-AT target genes, (4) signalling pathways leading to NF-AT activation: the role of protein kinases and calcineurin, (5) the nuclear entry and exit of NF-AT factors, (6) transcriptional transactivation by NF-AT factors, (7) the structure and expression of the chromosomal NF-AT2 gene, and (8) NF-AT factors in Th cell differentiation. The experimental data presented and discussed in the review show that NF-AT factors are major players in the control of T cell activation and differentiation and, in all likelihood, also of the cell cycle and apoptosis of T lymphocytes.

Vav proteins, adaptors and cell signaling

“…Another possible interaction between Vav and the NF-AT response is in the regulation of the Ras pathway, a route previously shown to be important for the activation of this transcriptional factor (Ser¯ing et al, 2000;Zhu and McKeon, 2000). Ras is also important for Vav signaling, since the expression of a dominant negative mutant of Ras inhibits the activation of NF-AT by Vav and Vav2 in lymphocytes (Doody et al, 2000;Wu et al, 1995).…”

“…These functions have been ®rmly established both by overexpression studies in cell lines and by loss-offunction mutations using gene targeting experiments Costello et al, 1999;Fischer et al, 1995Fischer et al, , 1998Turner et al, 1997;Wu et al, 1995). These two functions are probably intertwined during signal transduction, given the known connection between Ca 2+¯u xes and NF-AT activation in lymphocytes (Ser¯ing et al, 2000;Zhu and McKeon, 2000). There is recent evidence indicating that this biological response includes Rho/Rac-independent steps.…”

“…The answer to this question is di cult due to the complexity of the NF-AT pathway in T-cells. This transcriptional factor becomes activated by the conversion of three independent pathways that mediate both its subcellular localization and transcriptional activity (Ser¯ing et al, 2000;Zhu and McKeon, 2000). First, NF-AT activation requires the generation of Ca 2+¯u xes that mediate the activation of calcineurin.…”

“…This molecule is a Ca 2+ -dependent serine phosphatase that dephosphorylates NF-AT molecules in a cluster of serine residues, a necessary step for the translocation of this transcriptional factor to the nucleus. Once in the nucleus, NF-AT requires the help of converging signals from the Rac1 and Ras pathways for the transcriptional activation of target genes (Ser¯ing et al, 2000;Zhu and McKeon, 2000). Fragmentary evidence indicates that Vav protein can impinge on NF-AT function at di erent levels: (i) changes in the cytoskeleton; (ii) activation of calcium¯uxes; (iii) activation of the Ras pathway; (iv) other adaptor proteins (Figure 2).…”

Selective inhibition of calcineurin-NFAT signaling by blocking protein–protein interaction with small organic molecules

“…Calcineurin, a phosphoprotein phosphatase, is poised at a branch point of calcium͞calmodulin signaling and controls the function of diverse effector proteins, ranging from transcription factors to enzymes, transmembrane ion channels, and proteins involved in apoptosis (25,26). Its effectors include the four NFAT-family proteins, transcription factors that activate cytokine gene expression in T cells (27)(28)(29)(30) and that also participate in the genetic programs of muscle fiber-type specialization, osteoclast differentiation, cardiac valve development, and myocardial hypertrophy (29)(30)(31)(32). The conventional method of blocking calcineurin-NFAT signaling is to apply the immunosuppressive compounds cyclosporin A (CsA) and FK506, which, in the form of CsA-cyclophilin or FK506-FKBP12 complexes, inhibit the enzymatic activity of calcineurin toward all its physiological substrates (33).…”