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J. Biol. Chem., Vol. 279, Issue 48, 49571-49574, November 26, 2004

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Phosphorylation of Serine 468 by GSK-3 Negatively Regulates Basal p65 NF-B Activity^*

Holger Buss, Anneke Dörrie, M. Lienhard Schmitz, Ronald Frank¶, Mark Livingstone||, Klaus Resch, and Michael Kracht**

From the Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625, Hannover, Germany, the Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland, the ^¶Department of Chemical Biology, German Research Centre for Biotechnology (GBF), Mascheroder Weg 1, D-38124 Braunschweig, Germany, and ^||Cell Signaling Technology, Inc., Beverly, Massachusetts 01915

The activity of NF-B is controlled at several levels including the phosphorylation of the strongly transactivating p65 (RelA) subunit. However, the overall number of phosphorylation sites, the signaling pathways and protein kinases that target p65 NF-B and the functional role of these phosphorylations are still being uncovered. Using a combination of peptide arrays with in vitro kinase assays we identify serine 468 as a novel phosphorylation site of p65 NF-B. Serine 468 lies within a GSK-3 consensus site, and recombinant GSK-3 specifically phosphorylates a GST-p65-(354–551) fusion protein at Ser⁴⁶⁸ in vitro. In intact cells, phosphorylation of endogenous Ser⁴⁶⁸ of p65 is induced by the PP1/PP2A phosphatase inhibitor calyculin A and this effect is inhibited by the GSK-3 inhibitor LiCl. Reconstitution of p65-deficient cells with a p65 protein where serine 468 was mutated to alanine revealed a negative regulatory role of serine 468 for NF-B activation. Collectively our results suggest that a GSK-3-PP1-dependent mechanism regulates phosphorylation of p65 NF-B at Ser⁴⁶⁸ in unstimulated cells and thereby controls the basal activity of NF-B.

Received for publication, September 20, 2004 , and in revised form, September 29, 2004.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (KR1143/4-1, KR-1143/4-2, and SFB566/B06 (to M. K.) and Schm 1417/3-1, 3-2, 3-3 to (to L. S.)). The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Inst. of Pharmacology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Tel.: 49-511-532-2800; Fax: 49-511-532-4081; E-mail: kracht.michael{at}MH-hannover.de.

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