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Cited by 1,991Signaling Pathways in DiseaseGenomics and Chromatin DynamicsNuclear Receptors and Signaling

Transcriptional regulation by calcium, calcineurin, and NFAT

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Hogan, Patrick G., Chen, Lin, Nardone, Julie, Rao, Anjana·2003·Genes & Development
DOI 10.1101/gad.1102703
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Abstract

The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFATrelated protein represented in the Drosophila genome. NFAT5 is identical to TonEBP (tonicity element binding protein), a transcription factor crucial for cellular responses to hypertonic stress (Lopez-Rodriguez et al. 1999; Miyakawa et al. 1999). We focus here on the remaining four NFAT proteins (NFAT1–NFAT4, also known as NFATc1–c4; see Table 1), referring to them collectively as NFAT. The distinguishing feature of NFAT is its regulation by Ca and the Ca/calmodulin-dependent serine phosphatase calcineurin. NFAT proteins are phosphorylated and reside in the cytoplasm in resting cells; upon stimulation, they are dephosphorylated by calcineurin, translocate to the nucleus, and become transcriptionally active, thus providing a direct link between intracellular Ca signaling and gene expression. NFAT activity is further modulated by additional inputs from diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In the first part of this review, we describe the influence of these multiple inputs on the nuclear–cytoplasmic distribution and transcriptional function of NFAT. Recent structural data emphasize the remarkable versatility of NFAT binding to DNA. At composite NFAT:AP-1 elements found in the regulatory regions of many target genes, NFAT proteins bind cooperatively with an unrelated transcription factor, AP-1 (Fos–Jun; Chen et al. 1998). At DNA elements that resemble NF B sites, NFAT proteins bind DNA as dimers (Giffin et al. 2003; Jin et al. 2003). In the second section of this review, we describe these two modes of DNA binding by NFAT. NFAT also acts synergistically with transcription factors other than Fos and Jun, but the structural basis for synergy remains unknown. Drawing on published structures, we discuss the potential cooperation of NFAT with other classes of DNA-binding proteins. It is clear that NFAT activates transcription of a large number of genes during an effective immune response (Rao et al. 1997; Kiani et al. 2000; Serfling et al. 2000; Macian et al. 2001). In the third part of this review, we present information obtained from these studies, highlighting experimental and bioinformatics approaches to identifying NFAT target genes. We discuss the finding that NFAT and NFAT–Fos–Jun complexes activate distinct subsets of target genes in lymphocytes (Macian et al. 2002). We also describe a novel aspect of gene regulation by NFAT, in which this transcription factor participates in an early phase of chromatin remodeling that occurs at specific genetic loci in differentiating T cells (Avni et al. 2002). There is evidence that NFAT regulates cell differentiation programs in cell types other than immune cells (Crabtree and Olson 2002; Horsley and Pavlath 2002; Graef et al. 2003; Hill-Eubanks et al. 2003). In the last section of this review, we select three differentiation programs—fiber-type specification in differentiated skeletal muscle, cardiac valve development, and osteoclast differentiation—for detailed consideration. We evaluate the evidence for NFAT involvement, point out novel cellular and molecular mechanisms that might regulate this familiar transcription factor, and discuss how NFAT exerts its biological effects. Because the phenotypes of NFAT knockout mice have been reviewed elsewhere (Crabtree and Olson 2002; Horsley and Pavlath 2002), we refer to them only as necessary to illustrate specific points.

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  • In the canonical NFAT pathway, Ca2+/Calcineurin mediates nuclear translocation of NFAT through the dephosphorylation of multiple serine residues in the N-terminus region, including the nuclear localization signal.

    “In the canonical NFAT pathway, Ca2+/Calcineurin mediates nuclear translocation of NFAT through the dephosphorylation of multiple serine residues in the N-terminus region, including the nuclear localization signal (34, 59, 60).”

    From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [60]

    The ‘Ca²⁺ and calcineurin’ section says calcineurin dephosphorylates serines in NFAT’s N-terminal regulatory domain, triggering nuclear accumulation. The ‘Other considerations’ section links phosphorylation to exposure of the nuclear localization signal, but the copy does not say the signal itself is dephosphorylated; the Figure 2 caption identifies an SRR-2 phosphate that calcineurin does not remove. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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  1. Cockerill, P.N., Shannon, M.F., Bert, A.G., Ryan, G.R., and Va- das, M.A. 1993. The granulocyte-macrophage colony-stimu- lating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. Proc. Natl. Acad. Sci. 90: 2466-2470.
  2. Davidson, E.H. 2001. Genomic regulatory systems: Develop- ment and evolution. Academic Press, Boston, MA.
  3. Diehn, M., Alizadeh, A.A., Rando, O.J., Liu, C.L., Stankunas, K., Botstein, D., Crabtree, G.R., and Brown, P.O. 2002. Genomic expression programs and the integration of the CD28 co- stimulatory signal in T cell activation. Proc. Natl. Acad. Sci. 99: 11796-11801; erratum 99: 15245.
  4. Frey, N., Richardson, J.A., and Olson, E.N. 2000. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc. Natl. Acad. Sci. 97: 14632-14637.
  5. Giffin, M.J., Stroud, J.C., Bates, D., von Koenig, K.D., Hardin, J., and Chen, L. 2003. Structure of NFAT1 bound as a dimer to the HIV-1 LTR B element. Nat. Struct. Biol. (in press).
  6. Graef, I.A., Gastier, J.M., Francke, U., and Crabtree, G.R. 2001b. Evolutionary relationships among Rel domains indicate functional diversification by recombination. Proc. Natl. Acad. Sci. 98: 5740-5745.
  7. Hattersley, G. and Chambers, T.J. 1989. Calcitonin receptors as markers for osteoclastic differentiation: Correlation be- tween generation of bone-resorptive cells and cells that ex- press calcitonin receptors in mouse bone marrow cultures. Endocrinology 125: 1606-1612.
  8. Hsu, H., Lacey, D.L., Dunstan, C.R., Solovyev, I., Colombero, A., Timms, E., Tan, H.L., Elliott, G., Kelley, M.J., Sarosi, I., et al. 1999. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation in- duced by osteoprotegerin ligand. Proc. Natl. Acad. Sci. 96: 3540-3545.
  9. Jin, L., Sliz, P., Chen, L., Macián, F., Rao, A., Hogan, P.G., and Harrison, S.C. 2003. An asymmetric NFAT1 dimer on a pseudo-palindromic B-like DNA site. Nat. Struct. Biol. (in press).
  10. Kubis, H.P., Haller, E.A., Wetzel, P., and Gros, G. 1997. Adult fast myosin pattern and Ca 2+ -induced slow myosin pattern in primary skeletal muscle culture. Proc. Natl. Acad. Sci. 94: 4205-4210.
  11. López-Rodríguez, C., Aramburu, J., Rakeman, A.S., and Rao, A. 1999. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc. Natl. Acad. Sci. 96: 7214-7219.
  12. Miyakawa, H., Woo, S.K., Dahl, S.C., Handler, J.S., and Kwon, H.M. 1999. Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc. Natl. Acad. Sci. 96: 2538-2542.
  13. Pallafacchina, G., Calabria, E., Serrano, A.L., Kalhovde, J.M., and Schiaffino, S. 2002. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc. Natl. Acad. Sci. 99: 9213-9218.
  14. Park, S., Uesugi, M., and Verdine, G.L. 2000. A second calcineu- rin binding site on the NFAT regulatory domain. Proc. Natl. Acad. Sci. 97: 7130-7135.
  15. Peterson, B.R., Sun, L.J., and Verdine, G.L. 1996. A critical ar- ginine residue mediates cooperativity in the contact inter- face between transcription factors NFAT and AP-1. Proc. Natl. Acad. Sci. 93: 13671-13676.
  16. Serrano, A.L., Murgia, M., Pallafacchina, G., Calabria, E., Coni- glio, P., Lømo, T., and Schiaffino, S. 2001. Calcineurin con- trols nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth. Proc. Natl. Acad. Sci. 98: 13108-13113.
  17. Shaw, K.T., Ho, A.M., Raghavan, A., Kim, J., Jain, J., Park, J., Sharma, S., Rao, A., and Hogan, P.G. 1995. Immunosuppres- sive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc. Natl. Acad. Sci. 92: 11205-11209.
  18. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Mu- rakami, A., et al. 1998. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory fac- tor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. 95: 3597-3602.

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Authors
Hogan, P. G., Chen, L., Nardone, J., & Rao, A.
Affiliations
  • Harvard University (US)
  • University of Colorado Boulder (US)
  • Centre for Blood Research (CA)
Corresponding author
Rao, Anjana
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2003-09-15
Volume
17
Issue
18
Pages
2205-2232
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.1102703
OpenAlex
W2157973267
Cited by
1,991
References
6
Citations by year
2026: 53 · 2025: 58 · 2024: 66 · 2023: 66 · 2022: 58 · 2021: 95 · 2020: 115 · 2019: 91 · 2018: 101 · 2017: 105 · 2016: 87 · 2015: 108 · 2014: 92 · 2013: 113 · 2012: 108
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • W. M. Keck Foundation
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM064642)
  • National Institute of Allergy and Infectious Diseases (R21AI049905)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
NFAT transcription factors, calcineurin, calcium signaling, transcriptional regulation, Fos/Jun, transcriptional synergy, nuclear-cytoplasmic translocation, immune response genes
MeSH terms
Animals, Calcium, DNA-Binding Proteins, Nuclear Proteins, Transcription Factors, NF-kappa B, Mice, Knockout, Gene Expression Regulation, Developmental, Calcineurin, Genes, rel, NFATC Transcription Factors, Mice

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