FTDP-17 missense mutations site-specifically inhibit as well as promote dephosphorylation of microtubule-associated protein tau by protein phosphatases of HEK-293 cell extract

FTDP-17 missense tau mutations: G272V, P301L, V337M and R406W promote tau phosphorylation in human and transgenic mice brains by interfering with the tau phosphorylation/dephosphorylation balance. The effect of FTDP-17 mutations on tau phosphorylation by different kinases has been studied previously. However, it is not known how various FTDP-17 mutations affect tau dephosphorylation by phosphoprotein phosphatases. In this study we have observed that when transfected into HEK-293 cells, tau is phosphorylated on various sites that are also phosphorylated in diseased human brains. When transfected cells are lysed and incubated, endogenously phosphorylated tau is dephosphorylated by cellular protein phosphatase 1 (PP1), phosphatase 2A (PP2A) and phosphatase 2B (PP2B), which are also present in the lysate. By using this assay and specific inhibitors of PP1, PP2A and PP2B, we have observed that the G272V mutation promotes tau dephosphorylation by PP2A at Ser396/404, Ser235, Thr231, Ser202/205 and Ser214 and by PP2B at Ser214 but inhibits dephosphorylation by PP2B at Ser396/404. The P301L mutation promotes tau dephosphorylation at Thr231 by PP1 and at Ser396/404, Thr231, Ser235 and Ser202/205 by PP2A but inhibits dephosphorylation at Ser214 by PP2B. The V337M mutation promotes tau dephosphorylation at Ser235, Thr231 and Ser202/205 by PP2A and at Ser202/205 by PP2B whereas the R406W mutation promotes tau dephosphorylation at Ser396/404 by PP1, PP2A and PP2B but inhibits dephosphorylation at Ser202/205 and Ser235 by PP1 and PP2A, respectively. Our results indicate that each FTDP-17 tau mutation not only site-specifically inhibits tau dephosphorylation on some sites but also promotes dephosphorylation by phosphatases on other sites.