P1‐081: Tau decreases the phosphorylation of erk1/2 through recruiting and promoting the phosphatase activity of PP2A

The extracellular signal-regulated kinase 1/2 (ERK1/2) are serine/threonine kinases that participate in the Ras-Raf-MEK-ERK signal transduction cascade. Activity of ERK is phosphorylation regulated and dependent. Previous studies indicate that ERK activity is upstream of tau phosphorylation, whether tau also has a reversed regulatory effect on ERK remains elusive. Our preliminary data show that in tau knockout mice, phosphorylation level of ERK is significantly higher than that in wild type mice, indicating a role of tau in ERK regulation. The expression and phosphorylation level of ERK1/2 was detected in the hippocampus of wild type and tau mice by Western blotting. Purified phosphorylated ERK was incubated with brain homogenates from wild type or taumice, respectively. The amount and activity of ERK-binding phosphatases were measured through Co-immunoprecipitation assays and Serine/Threonine Phosphatase Assay System. ERK1/2 phosphorylation was enhanced in tau mice compared with that in wild type mice. Purified ERK in vitro dephosphorylation was inhibited in tau mice brain homogenate, which was reversed by addition of recombinant tau protein. Co-immunoprecipitation Assays and Serine/Threonine Phosphatase Assay showed that the level and activity of protein phosphatase 2A (PP2A) which in combination with ERK reduced in the brain homogenate of tau-/- mice compared to wild type mice. Tau inhibits the phosphorylation of ERK1/2 by recruiting PP2A to ERK and thus promoting the dephosphorylation of ERK by PP2A. These findings imply a new function of tau in the brain, thus provide important clues for understanding the role of tau in regulation of ERK and related cellular events.