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J. Biol. Chem., Vol. 277, Issue 50, 48664-48676, December 13, 2002
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From the The nuclear localization and transcriptional
activity of the NF-ATc family of transcription factors, essential to
many developmental, differentiation, and adaptation processes, are
determined by the opposing activities of the phosphatase calcineurin,
which promotes nuclear accumulation of NF-ATc, and several kinases,
which promote cytoplasmic accumulation. Many reports suggest that
protein kinase A (PKA) negatively modulates calcineurin-mediated NF-ATc
activation. Here we show that overexpression of PKA causes
phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct
opposition to calcineurin by phosphorylating Ser-245, Ser-269, and
Ser-294 in the conserved serine-proline repeat domain, and that
mutation of these serines blocks the effect of PKA. Activation of
endogenous PKA is similarly able to promote phosphorylation of these
sites on NF-ATc1 in two lymphoid cell lines. We further show that a complete block of NF-ATc1 nuclear localization by PKA requires a second
kinase activity that can be supplied by glycogen synthase kinase-3
(GSK-3), and that mutation of either the PKA phosphorylation sites or
the upstream GSK-3 sites prevents the effect of PKA. Thus, we propose
that PKA functions cooperatively as a priming kinase for further
phosphorylation by GSK-3 to oppose calcineurin-mediated nuclear
accumulation and transcriptional activity of NF-ATc1 and that,
through this mechanism, PKA may be an important modulator of many
NF-ATc-dependent processes.
Protein Kinase A Negatively Modulates the Nuclear Accumulation of
NF-ATc1 by Priming for Subsequent Phosphorylation by Glycogen Synthase
Kinase-3*
§,
,,§§
Program in Immunology, Department of
Molecular Pharmacology, Department of Medicine,
** Department of Pathology and Developmental Biology, Howard
Hughes Medical Institute, and ¶ Department of Neurobiology,
Stanford University, Stanford, California 94305
*
This work was supported by National Institutes of Health
Grant 5PO1AI36535 (to P. G.).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.
Present address: Cardiology Division, Massachusetts General
Hospital, Boston, MA 02114.
Present address: Pfizer, New London, CT 06333.
§§
To whom correspondence should be addressed. Tel.: 650-498-4826;
Fax: 650-724-7778; E-mail: pgardner@stanford.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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