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Molecular and Cellular Biology, May 2004, p. 4184-4195, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4184-4195.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Conserved Docking Motif for CK1 Binding Controls the Nuclear Localization of NFAT1

Heidi Okamura,1 Carmen Garcia-Rodriguez,1,{dagger} Holly Martinson,1 Jun Qin,2 David M. Virshup,3 and Anjana Rao1*

CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,1 Verna and Mars McLean Department of Biochemistry and Molecular Biology and the Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030,2 Department of Oncological Sciences, Huntsman Cancer Institute, and Department of Pediatrics, University of Utah, Salt Lake City, Utah 841123

Received 2 December 2003/ Returned for modification 5 January 2004/ Accepted 17 February 2004

In resting cells, the NFAT1 transcription factor is kept inactive in the cytoplasm by phosphorylation on multiple serine residues. These phosphorylated residues are primarily contained within two types of serine-rich motifs, the SRR-1 and SP motifs, which are conserved within the NFAT family. Several different kinases have been proposed to regulate NFAT, but no single candidate displays the specificity required to fully phosphorylate both types of motifs; thus, the identity of the kinase that regulates NFAT activity remains unclear. Here we show that the NFAT1 serine motifs are regulated by distinct kinases that must coordinate to control NFAT1 activation. CK1 phosphorylates only the SRR-1 motif, the primary region required for NFAT1 nuclear import. CK1 exists with NFAT1 in a high-molecular-weight complex in resting T cells but dissociates upon activation. GSK3 does not phosphorylate the SRR-1 region but can target the NFAT1 SP-2 motif, and it synergizes with CK1 to regulate NFAT1 nuclear export. We identify a conserved docking site for CK1 in NFAT proteins and show that mutation of this site disrupts NFAT1-CK1 interaction and causes constitutive nuclear localization of NFAT1. The CK1 docking motif is present in proteins of the Wnt, Hedgehog, and circadian-rhythm pathways, which also integrate the activities of CK1 and GSK3.

* Corresponding author. Mailing address: CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Ave., Rm. 144, Boston, MA 02115. Phone: (617) 278-3260. Fax: (617) 278-3280. E-mail: arao{at}cbr.med.harvard.edu.

{dagger} Present address: IBGM, Universidad de Valladolid, Valladolid, Spain.

Molecular and Cellular Biology, May 2004, p. 4184-4195, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4184-4195.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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