Abstract
The serine/threonine phosphatase 2A (PP2A) has been implicated in the pathogenesis of Alzheimer's disease (AD) due to its important role in regulating dephosphorylation of the microtubule-associated protein tau and mitogen-activated protein (MAP) kinase. In the present study, we show that PP2A was responsible for dephosphorylation of the extracellular signal-regulated kinase 1/2 (Erk1/2) following its activation by BK stimulation. Abnormal gene and protein expressions of PP2A, as well as its activity, were found to contribute to the abnormally prolonged Erk1/2 phosphorylation in the AD fibroblasts. Inhibition of PP2A with okadiac acid produced enhanced and more lasting Erk1/2 phosphorylation after BK stimulation, whereas FK506, an inhibitor of PP2B and FK-binding protein, inhibited the BK-stimulated Erk1/2 phosphorylation. Furthermore, while the phosphorylated Erk1/2 was concentrated in the nucleus of AC cells, it was mainly distributed in the extranuclear compartments of AD cells. These results suggest that the delayed dephosphorylation of Erk1/2 in AD cells following its BK-stimulated activation may be due to deficits of PP2A activity and impaired nuclear translocation of phosphorylated Erk1/2.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Aged
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Aged, 80 and over
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Alzheimer Disease / enzymology*
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology
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Cell Compartmentation / drug effects
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Cell Compartmentation / physiology
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Female
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Fibroblasts / drug effects
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Fibroblasts / enzymology*
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Fibroblasts / pathology
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Humans
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Immunohistochemistry
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Male
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Middle Aged
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Mitogen-Activated Protein Kinases / metabolism*
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Okadaic Acid / pharmacology
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Peptidylprolyl Isomerase / antagonists & inhibitors
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Peptidylprolyl Isomerase / metabolism
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation / drug effects
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Protein Phosphatase 2
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Tacrolimus / pharmacology
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Tacrolimus Binding Proteins / antagonists & inhibitors
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Tacrolimus Binding Proteins / metabolism
Substances
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Enzyme Inhibitors
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RNA, Messenger
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Okadaic Acid
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Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Tacrolimus Binding Proteins
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FKBP10 protein, human
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Peptidylprolyl Isomerase
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Tacrolimus