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I PP2A 1 Affects Tau Phosphorylation via Association with the Catalytic Subunit of Protein Phosphatase 2A*

By She Chen, Bin Li, Inge Grundke-Iqbal and Khalid Iqbal


In Alzheimer disease (AD) brain, the level of I PP2A1, a 249-amino acid long endogenous inhibitor of protein phosphatase 2A (PP2A), is increased, the activity of the phosphatase is decreased, and the microtubule-associated protein Tau is abnormally hyperphosphorylated. However, little is known about the detailed regulatory mechanism by which PP2A activity is inhibited by I PP2A1 and the consequent events in mammalian cells. In this study, we found that both I PP2A1 and its N-terminal half I PP2A(1–120)1, but neither I PP2A(1–163)1 nor I PP2A(164–249)1, inhibited PP2A activity in vitro, suggesting an autoinhibition by amino acid residues 121–163 and its neutralization by the C-terminal region. Furthermore, transfection of NIH3T3 cells produced a dose-dependent inhibition of PP2A activity by I PP2A1. I PP2A1 and PP2A were found to colocalize in PC12 cells. I PP2A1 could only interact with the catalytic subunit of PP2A (PP2Ac) and had no interaction with the regulatory subunits of PP2A (PP2A-A or PP2A-B) using a glutathione S-transferase-pulldown assay. The interaction was further confirmed by coimmunoprecipitation of I PP2A1 and PP2Ac from lysates of transiently transfected NIH3T3 cells. The N-terminal isotype specific region of I PP2A1 was required for its association with PP2Ac as well as PP2A inhibition. In addition, the phosphorylation of Tau was significantly increased in PC12/Tau441 cells transiently transfected with full-length I PP2A1 and with PP2Ac-interacting I PP2A1 deletion mutant 1–120 (I PP2A1ΔC2). Double immunofluorescence staining showed that I PP2A1 and I PP2A1ΔC2 increased Tau phosphorylation and impaired the microtubule network and neurite outgrowth in PC12 cells treated with nerve growth factor

Topics: Enzyme Catalysis and Regulation
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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