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J. Biol. Chem., Vol. 283, Issue 10, 6288-6299, March 7, 2008

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Fyn Modulation of Dab1 Effects on Amyloid Precursor Protein and ApoE Receptor 2 Processing^*

Hyang-Sook Hoe¹, S. Sakura Minami¹, Alexandra Makarova^¶, Jiyeon Lee^||, Bradley T. Hyman^¶, Yasuji Matsuoka, and G. William Rebeck²

From the Department of Neuroscience and the Department of Neurology, Georgetown University Medical Center, Washington, D. C. 20057, the ^¶Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disorders, Charlestown, Massachusetts, 02129, and the ^||Departments of Pediatrics and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Dab1 is an intracellular adaptor protein that interacts with amyloid precursor protein (APP) and apoE receptor 2 (apoEr2), increases their levels on the cell surface, and increases their cleavage by -secretases. To investigate the mechanism underlying these alterations in processing and trafficking of APP and apoEr2, we examined the effect of Fyn, an Src family-tyrosine kinase known to interact with and phosphorylate Dab1. Co-immunoprecipitation, co-immunostaining, and fluorescence lifetime imaging demonstrated an association between Fyn and APP. Fyn induced phosphorylation of APP at Tyr-757 of the ⁷⁵⁷YENPTY⁷⁶² motif and increased cell surface expression of APP. Overexpression of Fyn alone did not alter levels of sAPP or cytoplasmic C-terminal fragments, although it significantly decreased production of Aβ. However, in the presence of Dab1, Fyn significantly increased sAPP and C-terminal fragments. Fyn-induced APP phosphorylation and cell surface levels of APP were potentiated in the presence of Dab1. Fyn also induced phosphorylation of apoEr2 and increased its cell surface levels and, in the presence of Dab1, affected processing of its C-terminal fragment. In vivo studies showed that sAPP was decreased in the Fyn knock-out, supporting a role for Fyn in APP processing. These data demonstrate that Fyn, due in part to its effects on Dab1, regulates the phosphorylation, trafficking, and processing of APP and apoEr2.

Received for publication, May 21, 2007 , and in revised form, December 14, 2007.

^* This work was supported by National Institutes of Health Grants AG14473 (to G. W. R.) and AG022455 (to Y. M.) and by an Intramural Aging Grant at Georgetown University (to H.-S. H.) and a fund for Alzheimer research established in memory of Bill and Marie Drach. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd. NW, Washington, D. C. 20057-1464. Tel.: 202-687-1534; Fax: 202-687-0617; E-mail: gwr2{at}georgetown.edu.

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