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J. Biol. Chem., Vol. 281, Issue 46, 35176-35185, November 17, 2006

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DAB1 and Reelin Effects on Amyloid Precursor Protein and ApoE Receptor 2 Trafficking and Processing^*

Hyang-Sook Hoe, Tracy S. Tran, Yasuji Matsuoka^¶, Brian W. Howell, and G. William Rebeck¹

From the Department of Neuroscience and the ^¶Department of Neurology, Georgetown University Medical Center, Washington, D. C. 20057-1464 and Neurogenetics Branch, NINDS Porter Neuroscience Research Center, National Institutes of Health, Bethesda, Maryland 20892-3705

Numerous cytoplasmic adaptor proteins, including JIP1, FE65, and X11, affect amyloid precursor protein (APP) processing and A production. Dab1 is another adaptor protein that interacts with APP as well as with members of the apoE receptor family. We examined the effect of Dab1 on APP and apoEr2 processing in transfected cells and primary neurons. Dab1 interacted with APP and apoEr2 and increased levels of their secreted extracellular domains and their cytoplasmic C-terminal fragments. These effects depended on the NPXY domains of APP and apoEr2 and on the phosphotyrosine binding domain of Dab1 but did not depend on phosphorylation of Dab1. Dab1 decreased the levels of APP -C-terminal fragment and secreted A. Full-length Dab1 or its phosphotyrosine binding domain alone increased surface levels of APP, as determined by surface protein biotinylation and live cell staining. A ligand for apoEr2, the extracellular matrix protein Reelin, significantly increased the interaction of apoEr2 with Dab1. Surprisingly, we also found that Reelin treatment significantly increased the interaction of APP and Dab1. Moreover, Reelin treatment increased cleavage of APP and apoEr2 and decreased production of the -C-terminal fragment of APP and A. Together, these data suggest that Dab1 alters trafficking and processing of APP and apoEr2, and this effect is influenced by extracellular ligands.

Received for publication, March 7, 2006 , and in revised form, July 6, 2006.

^* This work was supported by National Institutes of Health Grants R01 AG14473 (to G. W. R.) and K01 AG022455 (to Y. M.). 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 To whom correspondence should be addressed: Dept. of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, D. C. 20057-1464. Tel.: 202-687-1534; Fax: 202-687-0617; E-mail: gwr2{at}georgetown.edu.

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