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hFE65L Influences Amyloid Precursor Protein Maturation and Secretion
Author(s) -
Guénette Suzanne Y,
Chen Jing,
Ferland Amber,
Haass Christian,
Capell Anja,
Tanzi Rudolph E.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0730985.x
Subject(s) - amyloid precursor protein , secretion , alpha secretase , microbiology and biotechnology , amyloid precursor protein secretase , p3 peptide , internalization , endocytic cycle , biology , chemistry , endocytosis , alzheimer's disease , biochemistry , cell , medicine , disease
: The amyloid precursor protein (APP) is processed in the secretory and endocytic pathways, where both the neuroprotective α‐secretase‐derived secreted APP (APPsα) and the Alzheimer’s disease‐associated β‐amyloid peptide are generated. All three members of the FE65 protein family bind the cytoplasmic domain of APP, which contains two sorting signals, YTS and YENPTY. We show here that binding of APP to the C‐terminal phosphotyrosine interaction domain of hFE65L requires an intact YENPTY clathrin‐coated pit internalization sequence. To study the effects of the hFE65L/APP interaction on APP trafficking and processing, we performed pulse/chase experiments and examined APP maturation and secretion in an H4 neuroglioma cell line inducible for expression of the hFE65L protein. Pulse/chase analysis of endogenous APP in these cells showed that the ratio of mature to total cellular APP increased after the induction of hFE65L. We also observed a threefold increase in the amount of APPsα recovered from conditioned media of cells overexpressing hFE65L compared with uninduced controls. The effect of hFE65L on the levels of APPsα secreted is due neither to a simple increase in the steady‐state levels of APP nor to activation of the protein kinase C‐regulated APP secretion pathway. We conclude that the effect of hFE65L on APP processing is due to altered trafficking of APP as it transits through the secretory pathway.