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J. Biol. Chem., Vol. 280, Issue 18, 18525-18535, May 6, 2005

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A Novel Protein Kinase B (PKB)/AKT-binding Protein Enhances PKB Kinase Activity and Regulates DNA Synthesis^*

Motonobu Anai, Nobuhiro Shojima, Hideki Katagiri¶, Takehide Ogihara¶, Hideyuki Sakoda, Yukiko Onishi, Hiraku Ono, Midori Fujishiro, Yasushi Fukushima, Nanao Horike||, Amelia Viana||, Masatoshi Kikuchi, Noriko Noguchi**, Shinichiro Takahashi, Kuniaki Takata, Yoshitomo Oka¶, Yasunobu Uchijima||, Hiroki Kurihara||, and Tomoichiro Asano||¶¶

From the Department of Internal Medicine, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1, Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan, the ^¶Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan, the Department of Cell Biology, Institute for Cellular and Molecular Regulation, Gunma University, 3-39-15 Showamachi, Maebashi, Gunma 371-8512, Japan, and the Department of Internal Medicine, Graduate School of Medicine, ^**Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, and ^||Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Protein kinase B (PKB)/Akt reportedly plays a role in the survival and/or proliferation of cells. We identified a novel protein, which binds to PKB, using a yeast two-hybrid screening system. This association was demonstrated not only in vivo by overexpressing both proteins or by coimmunoprecipitation of the endogenous proteins, but also in vitro using glutathione S-transferase fusion proteins. Importantly, this protein specifically associates with the C terminus of PKB but not with other AGC kinases and enhances PKB phosphorylation and kinase activation without growth factor stimulation. Thus, we termed this Akt-specific binding protein APE (Akt-phosphorylation enhancer). Since APE-induced phosphorylation of PKB did not occur in cells treated with wortmannin or LY294002, APE itself is not a kinase but seems to enhance or prolong the phosphoinositide 3-kinase-dependent phosphorylation of PKB. In cells in which APE was suppressed by small interfering RNA, DNA synthesis was significantly reduced with suppression of PKB phosphorylation, suggesting a synergistic role of APE in PKB-induced proliferation. On the other hand, in cells overexpressing both PKB and APE, despite markedly increased basal phosphorylation of PKB, both DNA rereplication and subsequent Chk2 phosphorylation and apoptosis were seen, suggesting the involvement of APE in the regulation of cell cycling replication licensing. Taking these observations together, APE appears to be a novel regulator of PKB phosphorylation. Furthermore, the interaction between APE and PKB, possibly dependent on the expression levels of both proteins, may be a novel molecular mechanism leading to proliferation and/or apoptosis.

Received for publication, January 18, 2005

^* This work was supported in part by a grant from Takeda Science Foundation. 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: Dept. of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-5841-3603; Fax: 81-3-5803-1874; E-mail: asano-tky{at}umin.ac.jp.

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