Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform.
The aberrant expression or processing of the amyloid precursor protein (APP) is the only known genetic basis for presenile familial Alzheimer's disease, and the molecular connection between APP and tau has been perplexing. Attention has focused on proline-directed serine/threonine kinases as mediating the cytoskeletal modifications of Alzheimer's disease, and we show that overexpression of APP can influence the activation of a candidate kinase, the mitogen-activated protein kinase (MAPK). In murine embryonal carcinoma cells stably transfected with the human 751 isoform of APP, we observed steady-state hyperactivation of p42(MAPK) concomitant with APP overexpression 3 days after neuroectodermal differentiation. In more mature differentiated cells, immunocytochemical analysis revealed enhanced basal somatic and nuclear immunoreactivity for phosphorylated MAPK coupled with an attenuated phosphorylation response to growth factor stimulation. Our results suggest that APP can influence the MAPK signaling pathway in such a way that the absolute and time-dependent activation required for discrimination of the appropriate downstream response are compromised. Such an effect would have important consequences for the functioning of cells coincidentally expressing both proteins, a situation that occurs in neuronal populations vulnerable to Alzheimer's disease pathology.
Grant
S M
SM
Department of Pharmacology and Therapeutics, McGill University, 3655 Drummond Street, Room 1325, Montreal, QC, Canada.
Morinville
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A
Maysinger
D
D
Szyf
M
M
Cuello
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AC
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018236:Carcinoma, Embryonal / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D004475:Ectoderm / Q000166:cytology / Q000187:drug effects*; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D016220:Fibroblast Growth Factor 1; D014212:Tretinoin; D006493:Heparin; D019950:Mitogen-Activated Protein Kinase 1