Nuclear Accumulation of NFAT4 Opposed by the JNK Signal Transduction Pathway
Abstract
The nuclear factor of activated T cells (NFAT) group of transcription factors is retained in the cytoplasm of quiescent cells. NFAT activation is mediated in part by induced nuclear import. This process requires calcium-dependent dephosphorylation of NFAT caused by the phosphatase calcineurin. The c-Jun amino-terminal kinase (JNK) phosphorylates NFAT4 on two sites. Mutational removal of the JNK phosphorylation sites caused constitutive nuclear localization of NFAT4. In contrast, JNK activation in calcineurin-stimulated cells caused nuclear exclusion of NFAT4. These findings show that the nuclear accumulation of NFAT4 promoted by calcineurin is opposed by the JNK signal transduction pathway.
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Docking motifs from HePTP, MEF2A, and NFAT4 bind the MAPK docking groove.
“Docking motifs from these three proteins bind the MAPK docking groove (9,12,22).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [22]
Phosphorylation of MEF2A Thr312 and Thr319 by p38α and presumably ERK2 stimulates MEF2A-mediated transactivation, while phosphorylation of NFAT4 Ser163 and Ser165 by JNK promotes its translocation from nucleus to cytosol.
“Phosphorylation of two residues in MEF2A (Thr312 and Thr319) by p38α and presumably ERK2 stimulates MEF2A-mediated transactivation in cells, whereas phosphorylation of Ser163 and Ser165 in NFAT4 by JNK promotes its translocation from the nucleus to the cytosol (22,24).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [22]
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- Authors
- Chow, C.-W., Rincón, M., Cavanagh, J., Dickens, M., & Davis, R. J.
- Affiliations
- University of Vermont (US)
- C.-W. Chow, J. Cavanagh, M. Dickens, R. J. Davis, Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
- Corresponding author
- Davis, Roger J.
- Venue
- Science
- Published
- 1997-11-28
- Volume
- 278
- Issue
- 5343
- Pages
- 1638-1641
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2053010478
- Cited by
- 357
- References
- 24
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 11 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 8 · 2013: 3 · 2012: 15
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health (5r01ca058396-09)
- National Cancer Institute (CA 58396, CA65831)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- NFAT4, NFAT, c-Jun N-terminal kinase, calcineurin, JNK phosphorylation, nuclear import, nuclear accumulation, transcription factor regulation, signal transduction
- MeSH terms
- Animals, Binding Sites, Cell Line, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Humans, Mutation, Nuclear Proteins, Phosphorylation, Protein Kinases, Recombinant Fusion Proteins, T-Lymphocytes, Transcription Factors, Transcription, Genetic, Signal Transduction, Cyclosporine, Calcium-Calmodulin-Dependent Protein Kinases, Jurkat Cells, COS Cells, Calcineurin, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, JNK Mitogen-Activated Protein Kinases, NFATC Transcription Factors, Calcineurin Inhibitors
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