Event:1202

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Event Title

Hampered NFAT activation and following nuclear localization, Activation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
The Adverse Outcome Pathway on binding of FK506-binding protein 12 (FKBP12) by calcineurin inhibitors leading to immunosuppression KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

The nuclear factor of activated T cells (NFAT) is a substrate of calcineurin (Rao et al. 1997). A NFAT has an N-terminal with a plurality of SP motifs rich in serine and proline, which are controlled by means of phosphorylation and dephosphorylation. There is a nuclear localization signal (NLS) held between these SP regions as well as a nuclear export signal (NES) in the N-terminal adjacent to the SP motifs (Beals et al. 1997, Zhu and McKeon 1999, Serfling et al. 2000). SP motifs ordinarily phosphorylate, which covers the NLS and leaves NES exposed, so NFAT localizes in cytoplasm. When calcineurin activates through stimulus from outside the cell, it binds directly to the N-terminal of NFAT in cytoplasm, after which SP motifs dephosphorylate to expose NLS and cover NES, thereby promoting nuclear localization of NFAT (Matsuda and Koyasu 2000, Zhu and McKeon 1999). When T-cell activation takes place, T-cell receptor (TCR)-mediated stimulus increases the intracellular concentration of calcium and activates CnB, which subsequently induces CnA phosphatase activation, leading to dephosphorylation of NFAT followed by nuclear localization. FK506-FKBP complexes inhibit calcineurin phosphatase activation, thereby interfering with NFAT nuclear localization. In B cells, extracellular stimulus passes through the B-cell receptor (BCR) to increase the intracellular concentration of calcium, leading to NFAT nuclear localization in the same manner as T-cells (Bhattacharyya et al.2011).

How it is Measured or Detected

Inhibition of translocation of NFAT to the nucleus is detected by gel mobility shift assay using nuclear extracts and/or cytoplasmic extracts (Flanagan et al. 1991).

Evidence Supporting Taxonomic Applicability

NFAT expresses in B cells, mast cells, neutrophil granulocytes, dendritic cells, macrophages, and natural killer cells as well as T cells from mammalian species including humans and rodents (Rao et al. 1997).

References

[1] Rao, A., Luo, C., and Hogan, PG. (1997). Transcription factors of the NFAT family: regulation and function. Annual Review of Immunology 15: 707-47.

[2] Beals, C.R., Clipstone, N.A., Ho, S.N. and Crabtree, G.R. (1997). Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. Genes & development 11 (7): 824-34.

[3] Zhu, J. and McKeon, F. (1999). NF-AT activation requires suppression of Crm1-dependent export by calcineurin. Nature. 398(6724): 256-60.

[4] Serfling, E., Berberich-Siebelt, F., Chuvpilo, S., Jankevics, E., Klein-Hessling, S., Twardzik, T., and Avots, A., (2000). The role of NF-AT transcription factors in T cell activation and differentiation. Biochimica et Biophysica Act 1498 (1): 1-18.

[5] Matsuda, S., Koyasu, S. (2000). A second target of cyclosporin A and FK506. Tanpakushitsu kakusan koso. 45(11): 1823-1831.

[6] Flanagan, W.M., Corthésy, B., Bram, R.J. and Crabtree, G.R. (1991). Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352 (6338): 803-7.

[7] Bhattacharyya, S., Deb, J., Patra, A.K., Thuy Pham, D.A., Chen, W., Vaeth, M., Berberich-Siebelt, F., Klein-Hessling, S., Lamperti, E.D., Reifenberg, K., Jellusova, J., Schweizer, A., Nitschke, L., Leich, E., Rosenwald, A., Brunner, C., Engelmann, S., Bommhardt, U., Avots, A., Müller, M.R., Kondo, E. and Serfling, E. (2011). NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network. The Journal of experimental medicine 208 (4): 823-39.