Inhibition of PP2A by hesperetin contributes to Akt and ERK1/2 activation in primary cortical neurons

Vauzour, David, Corsini, Simone, Müller, Michael and Spencer, Jeremy P E (2018) Inhibition of PP2A by hesperetin contributes to Akt and ERK1/2 activation in primary cortical neurons. Archives of Biochemistry and Biophysics, 650. pp. 14-21. ISSN 0003-9861

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Abstract

Flavonoids and their metabolites are well reported to modulate the activation/phosphorylation of various cellular kinases, such as ERK1/2 and JNK, although the mechanism by which they do so is unclear. In this study, we investigated the impact of flavanones on the activation of PI3K/Akt and ERK1/2 and determine whether this is mediated, in part, by the inhibition of phosphatases. Primary cortical neurons were exposed to physiological concentrations of hesperetin and the phosphorylation status of the kinases PI3K/Akt and ERK1/2 and the phosphatases PP2A and PTEN were assessed by immunoblotting after 30 min. Exposure to 100–300 nM hesperetin led to significant increases in the phosphorylation of ERK1/2 and Akt and significant decreases in PP2A levels and enzyme activity. Using in silico docking, hesperetin was found to fit into the active site of PP2A interacting within the hydrophobic cage of the catalytic unit. These data suggest a potential mechanism by which flavanones may lead to increased activation of ERK1/2 and Akt, commonly observed in cell models. Their interaction with and inhibition of cellular phosphatases counteract normal physiological regulation of signaling pathway activation thus facilitating and/or maintaining the activation status of ERK1/2 and Akt, important regulators of brain functions.

Item Type: Article
Uncontrolled Keywords: flavonoids,brain,signaling pathways,phosphatase,map kinase
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: Pure Connector
Date Deposited: 09 May 2018 10:30
Last Modified: 17 Jul 2020 23:38
URI: https://ueaeprints.uea.ac.uk/id/eprint/66969
DOI: 10.1016/j.abb.2018.04.020

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