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Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing

Excessive generation of amyloid-β peptide (Aβ) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phospho-adaptor protein that interacts with APP and has been shown to modulate APP processing. However, the...

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Autores principales: Lee, Yat Shing, Chow, Wan Ning Vanessa, Lau, Kwok-Fai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622059/
https://www.ncbi.nlm.nih.gov/pubmed/28963516
http://dx.doi.org/10.1038/s41598-017-12334-2
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author Lee, Yat Shing
Chow, Wan Ning Vanessa
Lau, Kwok-Fai
author_facet Lee, Yat Shing
Chow, Wan Ning Vanessa
Lau, Kwok-Fai
author_sort Lee, Yat Shing
collection PubMed
description Excessive generation of amyloid-β peptide (Aβ) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phospho-adaptor protein that interacts with APP and has been shown to modulate APP processing. However, the mechanism(s) that FE65 alters APP processing is still not fully understood. In the present study, we demonstrate that FE65 is phosphorylated at threonine 579 (T579) by glycogen synthase kinase 3β (GSK3β). Moreover, FE65 T579 phosphorylation potentiates γ- and β-secretases-mediated APP processing and Aβ liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3β stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579.
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spelling pubmed-56220592017-10-12 Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing Lee, Yat Shing Chow, Wan Ning Vanessa Lau, Kwok-Fai Sci Rep Article Excessive generation of amyloid-β peptide (Aβ) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phospho-adaptor protein that interacts with APP and has been shown to modulate APP processing. However, the mechanism(s) that FE65 alters APP processing is still not fully understood. In the present study, we demonstrate that FE65 is phosphorylated at threonine 579 (T579) by glycogen synthase kinase 3β (GSK3β). Moreover, FE65 T579 phosphorylation potentiates γ- and β-secretases-mediated APP processing and Aβ liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3β stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579. Nature Publishing Group UK 2017-09-29 /pmc/articles/PMC5622059/ /pubmed/28963516 http://dx.doi.org/10.1038/s41598-017-12334-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lee, Yat Shing
Chow, Wan Ning Vanessa
Lau, Kwok-Fai
Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title_full Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title_fullStr Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title_full_unstemmed Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title_short Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
title_sort phosphorylation of fe65 at threonine 579 by gsk3β stimulates amyloid precursor protein processing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622059/
https://www.ncbi.nlm.nih.gov/pubmed/28963516
http://dx.doi.org/10.1038/s41598-017-12334-2
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