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J. Biol. Chem., Vol. 279, Issue 23, 24343-24354, June 4, 2004

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Coordinated Metabolism of Alcadein and Amyloid -Protein Precursor Regulates FE65-dependent Gene Transactivation^*

Yoichi Araki, Naomi Miyagi, Naoko Kato, Tomohiro Yoshida, Sachiyo Wada, Masaki Nishimura¶, Hiroto Komano||, Tohru Yamamoto**, Bart De Strooper, Kazuo Yamamoto, and Toshiharu Suzuki¶¶

From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita-12 Nishi-6, Sapporo 060-0812, Japan, the Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan, the ^¶Neurology Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan, the ^||Department of Dementia Research, National Institute for Longevity Science, 36-3, Gengo, Morioka, Obu, Aichi 474-8522, Japan, the ^**Laboratory for Cell Asymmetry, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima Minatomachi, Chuo-ku, Kobe 650-0047, Japan, the Neuronal Cell Biology Laboratory, K. U. Leuven and Flanders Interuniversitary Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium, and the Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwanoha 5-1-5, Kashiwa, Chiba 277-8562, Japan

The Alcadeins (Alcs)/calsyntenins and the amyloid -protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent -cleavage that leads to the secretion of the amyloid -protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid -protein may contribute to neural disorders.

Received for publication, February 22, 2004

^* This work was supported by a Grant-in-aid for Scientific Research Area-Advanced Brain Science Project 15016002 (to T. S.) from the Ministry of Education, Science, Culture, Sports, and Technology, Japan and by a grant from The Naito Foundation (to T. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures.

^¶¶ To whom correspondence should be addressed. Tel.: 81-11-706-3250; Fax: 81-11-706-4991; E-mail: tsuzuki{at}pharm.hokudai.ac.jp.

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