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Molecular and Cellular Biology, November 2003, p. 7780-7793, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7780-7793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of NAP1, a Regulatory Subunit of I{kappa}B Kinase-Related Kinases That Potentiates NF-{kappa}B Signaling

Fumitaka Fujita,1,2 Yuko Taniguchi,1 Takashi Kato,1,2 Yasuko Narita,1 Akiko Furuya,3 Tatsuhiro Ogawa,3 Hiroaki Sakurai,4 Takashi Joh,2 Makoto Itoh,2 Mireille Delhase,5 Michael Karin,5 and Makoto Nakanishi1*

Department of Biochemistry and Cell Biology,1 Department of Medicine, Graduate School of Medicine, Nagoya City University, Mizuho-ku, Nagoya 467-8601,2 Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Machida, Tokyo 194-8533,3 Department of Pathogenic Biochemistry, Institute for Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-0194, Japan,4 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla, California 92093-06365

Received 30 January 2003/ Returned for modification 25 March 2003/ Accepted 15 July 2003

The I{kappa}B kinase (IKK)-related kinase NAK (also known as TBK or T2K) contributes to the activation of NF-{kappa}B-dependent gene expression. Here we identify NAP1 (for NAK-associated protein 1), a protein that interacts with NAK and its relative IKK{varepsilon} (also known as IKKi). NAP1 activates NAK and facilitates its oligomerization. Interestingly, the NAK-NAP1 complex itself effectively phosphorylated serine 536 of the p65/RelA subunit of NF-{kappa}B, and this activity was stimulated by tumor necrosis factor alpha (TNF-{alpha}). Overexpression of NAP1 specifically enhanced cytokine induction of an NF-{kappa}B-dependent, but not an AP-1-dependent, reporter. Depletion of NAP1 reduced NF-{kappa}B-dependent reporter gene expression and sensitized cells to TNF-{alpha}-induced apoptosis. These results define NAP1 as an activator of IKK-related kinases and suggest that the NAK-NAP1 complex may protect cells from TNF-{alpha}-induced apoptosis by promoting NF-{kappa}B activation.

* Corresponding author. Mailing address: Department of Biochemistry and Cell Biology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Phone: 81-52-853-8144. Fax: 81-52-842-3955. E-mail: mkt-naka{at}med.nagoya-cu.ac.jp.

Molecular and Cellular Biology, November 2003, p. 7780-7793, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7780-7793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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