This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Okamura, H. Articles by Rao, A. Search for Related Content PubMed PubMed Citation Articles by Okamura, H. Articles by Rao, A.

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

Heidi Okamura,¹ Carmen Garcia-Rodriguez,^1, Holly Martinson,¹ Jun Qin,² David M. Virshup,³ and Anjana Rao^1*

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.

Present address: IBGM, Universidad de Valladolid, Valladolid, Spain.

This article has been cited by other articles:

• Xu, S., Wong, C. C. L., Tong, E. H. Y., Chung, S. S. M., Yates, J. R. III, Yin, Y., Ko, B. C. B. (2008). Phosphorylation by Casein Kinase 1 Regulates Tonicity-induced Osmotic Response Element-binding Protein/Tonicity Enhancer-binding Protein Nucleocytoplasmic Trafficking. J. Biol. Chem. 283: 17624-17634 [Abstract] [Full Text]  
• Yang, T. T. C., Yu, R. Y. L., Agadir, A., Gao, G.-J., Campos-Gonzalez, R., Tournier, C., Chow, C.-W. (2008). Integration of Protein Kinases mTOR and Extracellular Signal-Regulated Kinase 5 in Regulating Nucleocytoplasmic Localization of NFATc4. Mol. Cell. Biol. 28: 3489-3501 [Abstract] [Full Text]  
• Xu, Y., Harton, J. A., Smith, B. D. (2008). CIITA Mediates Interferon-{gamma} Repression of Collagen Transcription through Phosphorylation-dependent Interactions with Co-repressor Molecules. J. Biol. Chem. 283: 1243-1256 [Abstract] [Full Text]  
• Srinivasan, M., Frauwirth, K. A. (2007). Reciprocal NFAT1 and NFAT2 Nuclear Localization in CD8+ Anergic T Cells Is Regulated by Suboptimal Calcium Signaling. J. Immunol. 179: 3734-3741 [Abstract] [Full Text]  
• Kim, E. Y., Ko, H. W., Yu, W., Hardin, P. E., Edery, I. (2007). A DOUBLETIME Kinase Binding Domain on the Drosophila PERIOD Protein Is Essential for Its Hyperphosphorylation, Transcriptional Repression, and Circadian Clock Function. Mol. Cell. Biol. 27: 5014-5028 [Abstract] [Full Text]  
• Shen, T., Cseresnyes, Z., Liu, Y., Randall, W. R., Schneider, M. F. (2007). Regulation of the nuclear export of the transcription factor NFATc1 by protein kinases after slow fibre type electrical stimulation of adult mouse skeletal muscle fibres. J. Physiol. 579: 535-551 [Abstract] [Full Text]  
• Bustos, V. H., Ferrarese, A., Venerando, A., Marin, O., Allende, J. E., Pinna, L. A. (2006). The first armadillo repeat is involved in the recognition and regulation of beta-catenin phosphorylation by protein kinase CK1. Proc. Natl. Acad. Sci. USA 103: 19725-19730 [Abstract] [Full Text]  
• SALAZAR, C., HOFER, T. (2006). Competition Effects Shape the Response Sensitivity and Kinetics of Phosphorylation Cycles in Cell Signaling. Ann. N. Y. Acad. Sci. 1091: 517-530 [Abstract] [Full Text]  
• He, Q., Cha, J., He, Q., Lee, H.-C., Yang, Y., Liu, Y. (2006). CKI and CKII mediate the FREQUENCY-dependent phosphorylation of the WHITE COLLAR complex to close the Neurospora circadian negative feedback loop. Genes Dev. 20: 2552-2565 [Abstract] [Full Text]  
• Dejmek, J., Safholm, A., Kamp Nielsen, C., Andersson, T., Leandersson, K. (2006). Wnt-5a/Ca2+-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1{alpha} Signaling in Human Mammary Epithelial Cells.. Mol. Cell. Biol. 26: 6024-6036 [Abstract] [Full Text]  
• Swiatek, W., Kang, H., Garcia, B. A., Shabanowitz, J., Coombs, G. S., Hunt, D. F., Virshup, D. M. (2006). Negative Regulation of LRP6 Function by Casein Kinase I {epsilon} Phosphorylation. J. Biol. Chem. 281: 12233-12241 [Abstract] [Full Text]  
• Tothova, J., Blaauw, B., Pallafacchina, G., Rudolf, R., Argentini, C., Reggiani, C., Schiaffino, S. (2006). NFATc1 nucleocytoplasmic shuttling is controlled by nerve activity in skeletal muscle. J. Cell Sci. 119: 1604-1611 [Abstract] [Full Text]  
• Shen, T., Liu, Y., Cseresnyes, Z., Hawkins, A., Randall, W. R., Schneider, M. F. (2006). Activity- and Calcineurin-independent Nuclear Shuttling of NFATc1, but Not NFATc3, in Adult Skeletal Muscle Fibers. Mol. Biol. Cell 17: 1570-1582 [Abstract] [Full Text]  
• Hwang, E. S., Hong, J.-H., Glimcher, L. H. (2005). IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508. J. Exp. Med. 202: 1289-1300 [Abstract] [Full Text]  
• Shirogane, T., Jin, J., Ang, X. L., Harper, J. W. (2005). SCF{beta}-TRCP Controls Clock-dependent Transcription via Casein Kinase 1-dependent Degradation of the Mammalian Period-1 (Per1) Proteinm. J. Biol. Chem. 280: 26863-26872 [Abstract] [Full Text]  
• Cyran, S. A., Yiannoulos, G., Buchsbaum, A. M., Saez, L., Young, M. W., Blau, J. (2005). The Double-Time Protein Kinase Regulates the Subcellular Localization of the Drosophila Clock Protein Period. J. Neurosci. 25: 5430-5437 [Abstract] [Full Text]  
• Ortega-Perez, I., Cano, E., Were, F., Villar, M., Vazquez, J., Redondo, J. M. (2005). c-Jun N-terminal Kinase (JNK) Positively Regulates NFATc2 Transactivation through Phosphorylation within the N-terminal Regulatory Domain. J. Biol. Chem. 280: 20867-20878 [Abstract] [Full Text]  
• Kattapuram, T., Yang, S., Maki, J. L., Stone, J. R. (2005). Protein Kinase CK1{alpha} Regulates mRNA Binding by Heterogeneous Nuclear Ribonucleoprotein C in Response to Physiologic Levels of Hydrogen Peroxide. J. Biol. Chem. 280: 15340-15347 [Abstract] [Full Text]  
• Yang, T. T. C., Xiong, Q., Graef, I. A., Crabtree, G. R., Chow, C.-W. (2005). Recruitment of the Extracellular Signal-Regulated Kinase/Ribosomal S6 Kinase Signaling Pathway to the NFATc4 Transcription Activation Complex. Mol. Cell. Biol. 25: 907-920 [Abstract] [Full Text]  
• Kafadar, K. A., Cyert, M. S. (2004). Integration of Stress Responses: Modulation of Calcineurin Signaling in Saccharomyces cerevisiae by Protein Kinase A. Eukaryot Cell 3: 1147-1153 [Abstract] [Full Text]