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J Biol Chem, Vol. 275, Issue 5, 3543-3551, February 4, 2000
From the Department of Microbiology-Immunology, Northwestern
University Medical School, Chicago, Illinois 60611
The subcellular localization of the transcription
factor NFATc is tightly regulated by the calcium-regulated phosphatase
calcineurin, which acts to directly dephosphorylate NFATc, causing its
rapid translocation from the cytoplasm to the nucleus. The
calcineurin-mediated nuclear localization of NFATc is opposed by poorly
defined protein kinases that act either to directly antagonize nuclear
import or, alternatively, to promote nuclear export. Here, we provide evidence that the cellular protein kinases JNK, ERK, p38, and CK2
(formerly casein kinase II) are involved in the regulation of NFATc
subcellular localization. We show that JNK, ERK, and p38 physically
associate with the NFATc N-terminal regulatory domain and can directly
phosphorylate functionally important residues involved in regulating
NFATc subcellular localization, namely Ser172 and the
conserved NFATc Ser-Pro repeats. Moreover, we found that overexpression
of JNK, ERK, or p38 is able to block ionomycin-induced NFATc nuclear
translocation, whereas treatment of cells with both PD98059 and
SB202190, which inhibit MAPK/SAPK signaling pathways, is sufficient to
trigger NFATc nuclear localization. Finally, we show that CK2 also
binds the N terminus of NFATc and phosphorylates functionally important
amino acid residues, including a conserved amino acid motif located
downstream of each of the NFATc Ser-Pro repeats that appears to be
important for regulating NFATc nuclear export. Collectively, these
studies identify functionally important amino acid residues and protein
kinases involved in the regulation of NFATc subcellular localization.
Identification of Amino Acid Residues and Protein Kinases
Involved in the Regulation of NFATc Subcellular Localization*
*
This work was supported in part by a Gramm travel fellowship
award from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (to C. M. P.) and by National Institutes of
Health Grant GM55292 (to N. A. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 312-503-8233;
Fax: 312-503-1339; E-mail: n-clipstone@nwu.edu.
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