title: Fyn kinase regulates the association between amyloid precursor protein and Dab1 by promoting their localization to detergent-resistant membranes.
abstract: The adaptor protein Disabled1 (Dab1) interacts with amyloid precursor protein (APP) and decreases its pathological processing, an effect mediated by Fyn tyrosine kinase. Fyn is highly enriched in lipid rafts, a major site of pathological APP processing. To investigate the role of Fyn in the localization and phosphorylation of APP and Dab1 in lipid rafts, we isolated detergent-resistant membrane (DRM) fractions from wild-type and Fyn knock-out mice. In wild-type mice, all of the Fyn kinase, 17% of total APP, and 33% of total Dab1 were found in DRMs. Nearly all of the tyrosine phosphorylated forms of APP and Dab1 were in DRMs. APP and Dab1 co-precipitated both in and out of DRM fractions, indicating an association that is independent of subcellular localization. Fyn knock-out mice had decreased APP, Dab1, and tyrosine-phosphorylated Dab1 in DRMs but increased co-immunoprecipitation of DRM APP and Dab1. Expression of phosphorylation deficient APP or Dab1 constructs revealed that phosphorylation of APP increases, whereas phosphorylation of Dab1 decreases, the interaction between APP and Dab1. Consistent with these observations, Reelin treatment led to increased Dab1 phosphorylation and decreased association between APP and Dab1. Reelin also caused increased localization of APP and Dab1 to DRMs, an effect that was not seen in Fyn knock-out neurons. These findings suggest that Reelin treatment promotes the localization of APP and Dab1 to DRMs, and affects their phosphorylation by Fyn, thus regulating their interaction.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia 20057-1464, USA.
authors.forename: S Sakura
authors.initials: SS
authors.lastname: Minami
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003902:Detergents / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D003902:Detergents; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D014443:Tyrosine; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases