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Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway

C W Chow1, M Rincón, J Cavanagh

  • 1Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Science (New York, N.Y.)
|December 31, 1997
PubMed

Insights

Nuclear import of nuclear factor of activated T cells (NFAT) is key for activation. The JNK pathway opposes calcineurin-mediated nuclear accumulation of NFAT4, revealing a critical regulatory mechanism.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Nuclear factor of activated T cells (NFAT) proteins reside in the cytoplasm of inactive cells.
  • NFAT activation involves translocation to the nucleus, a process regulated by calcium signaling and calcineurin phosphatase activity.

Purpose of the Study:

  • To investigate the role of c-Jun amino-terminal kinase (JNK) in regulating NFAT4 nuclear localization.
  • To elucidate the interplay between calcineurin and JNK signaling pathways in controlling NFAT4 cellular localization.

Main Methods:

  • Site-directed mutagenesis to alter JNK phosphorylation sites on NFAT4.
  • Analysis of NFAT4 localization in response to calcineurin stimulation and JNK activation.

Main Results:

  • Mutating JNK phosphorylation sites on NFAT4 resulted in its constitutive nuclear localization.
  • JNK activation in calcineurin-stimulated cells led to NFAT4 nuclear exclusion.
  • Demonstrated opposing effects of calcineurin and JNK on NFAT4 nuclear import.

Conclusions:

  • The JNK signaling pathway acts antagonistically to the calcineurin pathway in regulating NFAT4 nuclear accumulation.
  • JNK phosphorylation is a critical determinant of NFAT4 localization and, consequently, its transcriptional activity.

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