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J. Biol. Chem., Vol. 282, Issue 21, 15823-15832, May 25, 2007

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GSK3 Activity Modifies the Localization and Function of Presenilin 1^*

Kengo Uemura, Akira Kuzuya, Yoshiharu Shimozono, Nobuhisa Aoyagi, Koichi Ando, Shun Shimohama^¶1, and Ayae Kinoshita^||12

From the Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, the ^¶Department of Neurology, Sapporo Medical University, Sapporo 060-8556, and the ^||School of Health Sciences, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan

Presenilin 1, a causative gene product of familial Alzheimer disease, has been reported to be localized mainly in the endoplasmic reticulum and Golgi membranes. However, endogenous Presenilin 1 also localizes at the plasma membrane as a biologically active molecule. Presenilin 1 interacts with N-cadherin/-catenin to form a trimeric complex at the synaptic site through its loop domain, whose serine residues (serine 353 and 357) can be phosphorylated by glycogen synthase kinase 3. Here, we demonstrate that cell-surface expression of Presenilin 1/-secretase is enhanced by N-cadherin-based cell-cell contact. Physical interaction between Presenilin 1 and N-cadherin/-catenin plays an important role in this process. Glycogen synthase kinase 3-mediated phosphorylation of Presenilin 1 reduces its binding to N-cadherin, thereby down-regulating its cell-surface expression. Moreover, reduction of the Presenilin 1·N-cadherin·-catenin complex formation leads to an impaired activation of contact-mediated phosphatidylinositol 3-kinase/Akt cell survival signaling. Furthermore, phosphorylation of Presenilin 1 hinders -cleavage of N-cadherin, whereas -cleavage of APP remained unchanged. This is the first report that clarifies the regulatory mechanism of Presenilin 1/-secretase with respect to its subcellular distribution and its differential substrate cleavage. Because the cleavage of various membrane proteins by Presenilin 1/-cleavage is involved in cellular signaling, glycogen synthase kinase 3-mediated phosphorylation of Presenilin 1 should be deeply associated with signaling functions. Our findings indicate that the abnormal activation of glycogen synthase kinase 3 can reduce neuronal viability and synaptic plasticity via modulating Presenilin 1/N-cadherin/-catenin interaction and thus have important implications in the pathophysiology of Alzheimer disease.

Received for publication, November 20, 2006 , and in revised form, March 19, 2007.

^* 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 equally contributed to this work.

² To whom correspondence should be addressed: School of Health Sciences, Faculty of Medicine, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel./Fax: 81-75-751-3969; E-mail: akinoshita{at}hs.med.kyoto-u.ac.jp.

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