title: DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing.
abstract: Numerous cytoplasmic adaptor proteins, including JIP1, FE65, and X11alpha, affect amyloid precursor protein (APP) processing and Abeta 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 beta-C-terminal fragment and secreted Abeta. 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 beta-C-terminal fragment of APP and Abeta. Together, these data suggest that Dab1 alters trafficking and processing of APP and apoEr2, and this effect is influenced by extracellular ligands.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057-1464, USA.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Tran
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Brian W
authors.initials: BW
authors.lastname: Howell
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; D012697:Serine Endopeptidases