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J. Biol. Chem., Vol. 281, Issue 24, 16473-16481, June 16, 2006

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Akt Regulates Basal and Induced Processing of NF-B2 (p100) to p52^*

Jason A. Gustin¹, Chandrashekhar K. Korgaonkar¹, Roxana Pincheira^¶, Qiutang Li^¶, and David B. Donner²

From the Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Walther Cancer Institute, Indianapolis, Indiana 46208, and the ^¶Laboratory of Genetics, The Salk Institute, La Jolla, California 92037

NF-B is a family of transcription factors important for innate and adaptive immunity. NF-B is restricted to the cytoplasm by inhibitory proteins that are degraded when specifically phosphorylated, permitting NF-B to enter the nucleus and activate target genes. Phosphorylation of the inhibitory proteins is mediated by an IB kinase (IKK) complex, which can be composed of two subunits with enzymatic activity, IKK and IKK. The preferred substrate for IKK is IB, degradation of which liberates p65 (RelA) to enter the nucleus where it induces genes important to innate immunity. IKK activates a non-canonical NF-B pathway in which p100 (NF-B2) is processed to p52. Once produced, p52 can enter the nucleus and induce genes important to adaptive immunity. This study shows that Akt binds to and increases the activity of IKK and thereby increases p52 production in cells. Constitutively active Akt augments non-canonical NF-B activity, whereas kinase dead Akt or inhibition of phosphatidylinositol 3-kinase have the opposite effect. Basal and ligand-induced p52 production is reduced in mouse embryo fibroblasts deficient in Akt1 and Akt2 compared with parental cells. These observations show that Akt plays a role in activation of basal and induced non-canonical NF-B activity.

Received for publication, July 7, 2005 , and in revised form, March 24, 2006.

^* This work was supported by National Institutes of Health Grant CA 67891. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed (present address): Dept. of Surgery, University of California San Francisco, 1600 Divisadero St., Box 1932, San Francisco, CA 94143. Tel.: 415-353-9289; Fax: 415-353-9695; E-mail: donnerd{at}surgery.ucsf.edu.

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