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Molecular and Cellular Biology, July 2006, p. 5497-5508, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02469-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Ca2+/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-{kappa}B Activation{dagger}

Kazuhiro Ishiguro,1,3 Todd Green,4 Joseph Rapley,5 Heather Wachtel,1 Cosmas Giallourakis,1 Aimee Landry,2 Zhifang Cao,1,2 Naifang Lu,2 Ando Takafumi,3 Hidemi Goto,3 Mark J. Daly,4 and Ramnik J. Xavier1,2*

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114,1 Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114,2 Department of Therapeutic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan 466-8550,3 The Broad Institute of Harvard and Massachusetts Institute of Technology and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114,4 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 021145

Received 26 December 2005/ Returned for modification 2 February 2006/ Accepted 8 April 2006

CARMA1 is a central regulator of NF-{kappa}B activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-{kappa}B signaling downstream of the T-cell receptor (TCR). Computational analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca2+/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF-{kappa}B activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-{kappa}B activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF-{kappa}B activation.

* Corresponding author. Mailing address: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114. Phone: (617) 643-3331. Fax: (617) 643-3328. E-mail: Xavier{at}molbio.mgh.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2006, p. 5497-5508, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02469-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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